CN101589143A - Methods for treating hypercholesterolemia - Google Patents

Abstract

Disclosed herein are antisense compounds and methods for decreasing LDL-C in an individual having elevated LDL-C. Additionally disclosed are antisense compounds and methods for treating hypercholesterolemia, or alternatively for treating or preventing atherosclerosis. Further disclosed are antisense compounds and methods for decreasing coronary heart disease risk. Such methods include administering to an individual in need of treatment an antisense compound targeted to a PCSK9 nucleic acid. The antisense compounds administered include gapmer antisense oligonucleotides.

Description

The method that is used for the treatment of hypercholesterolemia

Invention field

The invention provides the method for the LDL-C level that is used for reducing the individuality that the LDL-C level raises.These class methods can be further used for treating hypercholesterolemia and reduce coronary heart disease risk.

Background of invention

Atherosclerosis is a kind of complexity, polygenic arteriasis disease, and it can cause coronary heart disease (CHD).In Western society, the complication that is caused by atherosclerosis is the modal cause of the death.Improve several risks and assumptions having established CHD, comprised LDL-C (LDL-C) rising, low-level highdensity lipoprotein-cholesterol (HDL-C), smoking, hypertension, age and early stage (early) CHD family history.In view of abundant clinical data and epidemiological study indication reduce the prevention that LDL-C is of value to unfavorable coronary artery events, the major objective (target) of the pharmacological intervention in CHD treatment and the prevention is to reduce LDL-C.

In the individuality of suffering from autosomal dominant hypercholesterolemia (ADH), the LDL-C level is raise and coding LDL-acceptor (LDL-R), apolipoprotein B (apoB) or preceding convertase subtilisin/kexin type 9 (proprotein convertase subtilisin/kexin type 9, PCSK9) sudden change in the gene connects (Abifadel et al., Nat.Genet., 2003,34:154-156).PCSK9 gene (being also referred to as FH3, NARCl, NARC-I and HCHOLA3) is positioned the Ip32.3 position of karyomit(e) 1.After gain-of-function mutation in finding PCSK9 and LDL-C level raise and be related, PCSK9 was accredited as the 3rd locus relevant with ADH.ApoB-100 participates in being rich in the interior assembling of born of the same parents and the secretion of tri-glyceride lipoprotein, and is the part of LDL-R.Someone proposes the LDL-R expression level in the PCSK9 reduction liver.LDL-R express to reduce and to cause liver that the picked-up of the lipoprotein that contains apoB-100 in the circulation is reduced, and causes cholesterol to raise then.

Familial hypercholesterolemia (FH) is caused by hundreds of different sudden changes among the LDL-R, and phenotypic characteristic is that blood plasma LDL-C level raises and the deposition of LDL-C in tendon, skin and artery, causes premature infant's cardiovascular disorder (premature cardiovascular disease).Isozygotying among the LDL-R is relevant with FH with heterozygous mutant.Similarly, the heterozygosis in the ligand binding domains of PCSK9 is relevant with the FH phenotype with purified mutant.Sudden change in this gene and the 3rd type autosomal dominant FH are connected.

In PCSK9 hereditary defect mouse, observe significant LDL-R and express rising and the rising of blood plasma LDL clearance rate.On the contrary, wild-type PCSK9 or some PCSK9 mutant crossing in mouse expressed and promoted LDL-R expression reduction and LDL-C level to raise.

Summary of the invention

Provide herein to be used for the treatment of hypercholesterolemia and/or atherosclerotic method, and be used to reduce the LDL-C level of rising and the method for CHD risk.The method that is used for the treatment of hypercholesterolemia comprises the antisense compounds of using target PCSK9 nucleic acid to individuality.In these class methods, the antisense compounds of target PCSK9 nucleic acid can target

Numbering NM_174936.2, The numbering NT_032977.8 Nucleotide 25475000-25504000 or Sequence shown in the numbering AK124635.1.

Be used for the treatment of and/or method that prevention of arterial is atherosis comprises the antisense compounds of using target PCSK9 nucleic acid to individuality.The method that is used to reduce the LDL-C level comprises the antisense compounds of using target PCSK9 nucleic acid to individuality.The method that is used to reduce the CHD risk comprises the antisense compounds of using target PCSK9 nucleic acid to individuality.These class methods can comprise the using of antisense compounds of the target PCSK9 nucleic acid for the treatment of significant quantity.

The method of the LDL-C level that is used for reducing the individuality that the LDL-C level raises is provided, has comprised, reduced the LDL-C level thus to the antisense oligonucleotide of the target PCSK9 nucleic acid of described individual administering therapeutic significant quantity.The method of the LDL-C level that is used for reducing individuality also is provided, has comprised the individuality of selecting the LDL-C level to raise, and given the antisense compounds of the target PCSK9 nucleic acid of described individual administering therapeutic significant quantity, and monitoring LDL-cholesterol levels.The atherosclerotic method that is used for the treatment of in the individuality further is provided, has comprised and select to suffer from atherosclerotic individuality, given the antisense compounds of the target PCSK9 nucleic acid of described individual administering therapeutic significant quantity, and the monitoring atherosclerosis.The method that is used to reduce coronary heart disease risk also is provided, the individuality that comprises one or more other indexs of the LDL-C level of selecting to have rising and coronary heart disease, give the antisense compounds of the target PCSK9 nucleic acid of described individual administering therapeutic significant quantity, and monitoring LDL-C level.The method that is used for the treatment of hypercholesterolemia also is provided, has comprised the antisense oligonucleotide of target PCSK9 nucleic acid that the individual administering therapeutic significant quantity of hypercholesterolemia is arranged to diagnosis, thus the reducing cholesterol level.

In any method that is provided, PCSK9 nucleic acid can be sequence shown in the SEQ ID NO:1.So, described antisense compounds can target SEQ ID NO:1 shown in PCSK9 nucleic acid.

Any method that is provided herein can further comprise monitoring LDL-C level.

If individuality shows the LDL-C level and is higher than 100mg/dL, is higher than 130mg/dL, is higher than 160mg/dL or is higher than 190mg/dL, then can select this individuality to use the antisense compounds of target PCSK9 nucleic acid.Using of the antisense compounds of target PCSK9 nucleic acid can cause the LDL-C level to be lower than 190mg/dL, is lower than 160mg/dL, is lower than 130mg/dL, is lower than 100mg/dL, is lower than 70mg/dL or is lower than 50mg/dL.

In any preceding method, the using of antisense compounds can comprise that parenteral uses.Parenteral is used and can further be comprised subcutaneous or intravenously is used.

In any method that is provided in this article, antisense compounds can have at least 80%, at least 90% or at least 95% complementarity with SEQ ID NO:1.Perhaps, antisense compounds can have 100% complementarity with SEQ ID NO:1.

Provided herein with any described method in the antisense compounds that adopted can a long 8-80 subunit (subunit), a long 12-50 subunit, a long 12-30 subunit, a long 15-30 subunit, a long 18-24 subunit, a long 19-22 subunit or long 20 subunits.Further, the antisense compounds that is adopted in any described method can be the antisense oligonucleotide of a long 8-80 Nucleotide, a long 12-50 Nucleotide, a long 12-30 Nucleotide, a long 15-30 Nucleotide, a long 18-24 Nucleotide, a long 19-22 Nucleotide or long 20 Nucleotide.

In any method that provides, antisense compounds can be an antisense oligonucleotide.In addition, antisense oligonucleotide can be breach polymers (gapmer) antisense oligonucleotide.Breach polymers antisense oligonucleotide can comprise and contain 52 '-the breach section that contains 10 2-deoxynucleotides between the pterion section of MOE Nucleotide.Breach polymers antisense oligonucleotide can be the antisense oligonucleotide that breach is widened, its comprise contain 32 '-between the pterion section of MOE contain 14 2 '-the breach section of deoxynucleotide.

In any method that provides, antisense compounds can have between at least one modified nucleosides and connects.In addition, connecting between each nucleosides can be to connect between the thiophosphatephosphorothioate nucleosides, and each cytosine(Cyt) can be a 5-methylcytosine.

The antisense compounds of target PCSK9 nucleic acid also is provided herein.The antisense oligonucleotide of target PCSK9 nucleic acid further is provided.Antisense compounds (comprising antisense oligonucleotide) can target PCSK9 nucleic acid, and it comprises

Numbering NM_174936.2,

The numbering NT_032977.8 Nucleotide 25475000-25504000 or

Sequence shown in the numbering AK124635.1.Antisense compounds (comprising antisense oligonucleotide) can have at least 70%, at least 80%, at least 90% or at least 95% complementarity with PCSK9 nucleic acid.Antisense compounds (comprising antisense oligonucleotide) can have 99% complementarity with PCSK9 nucleic acid.Antisense compounds (comprising antisense oligonucleotide) can have 100% complementarity with PCSK9 nucleic acid.For any antisense compounds that provides (comprising antisense oligonucleotide), PCSK9 nucleic acid can be the described sequence of SEQ ID NO:1.

The antisense compounds of target PCSK9 nucleic acid can a long 8-80 subunit, a long 12-50 subunit, a long 12-30 subunit, a long 15-30 subunit, a long 18-24 subunit, a long 19-22 subunit or long 20 subunits.The antisense oligonucleotide of target PCSK9 nucleic acid can a long 8-80 subunit, a long 12-50 subunit, a long 12-30 subunit, a long 15-30 subunit, a long 18-24 subunit, a long 19-22 subunit or long 20 subunits.

In addition, antisense compounds can be a breach polymers antisense oligonucleotide.Breach polymers antisense oligonucleotide can comprise and contain 52 '-the breach section that contains 10 2-deoxynucleotides between the pterion section of MOE Nucleotide.Breach polymers antisense oligonucleotide can be the antisense oligonucleotide that breach is widened, its comprise contain 32 '-between the pterion section of MOE contain 14 2 '-the breach section of deoxynucleotide.

The antisense compounds (comprising antisense oligonucleotide) of target PCSK9 nucleic acid can have between at least one modified nucleosides and connects.In addition, connecting between each nucleosides can be to connect between the thiophosphatephosphorothioate nucleosides.Each cytosine(Cyt) can be a 5-methylcytosine.

The antisense compounds (comprising antisense oligonucleotide) of target PCSK9 nucleic acid can have at least one modified nucleosides.In certain embodiments, modified nucleosides is sugar-modified Nucleotide (sugar-modifiednucleoside).In some such embodiment, sugar-modified nucleosides can further comprise natural or the heterocyclic base module of modifying and/or nucleosides natural or that modify between connect, and can comprise and be independent of sugar-modified further modification.In certain embodiments, sugar-modified nucleosides is 2 '-nucleosides modified, wherein the sugar ring from natural ribose or 2 '-2 ' carbon place of deoxidation-ribose is modified.

In certain embodiments, 2 ' nucleosides modified has 2 '-F, 2 '-OCH ₂(2 '-OMe) or 2-O (CH ₂) 2-OCH ₃(2 '-O-methoxyethyl or 2 '-MOE) substituting group.

In certain embodiments, 2 '-nucleosides modified has two cyclohexanol modules.In some such embodiment, two cyclohexanol modules are the D sugar of α configuration.In some such embodiment, two cyclohexanol modules are the D sugar of beta comfiguration.In certain embodiments, two cyclohexanol modules are the L sugar of α configuration.In some such embodiment, two cyclohexanol modules are the L sugar of beta comfiguration.

In certain embodiments, two cyclohexanol modules 2 ' and 4 '-comprise abutment group between the carbon atom.In some such embodiment, abutment group comprises 1-8 divalent group (biradical group) that is connected.In certain embodiments, two cyclohexanol modules comprise 1-4 divalent group that is connected.In certain embodiments, two cyclohexanol modules comprise 2 or 3 divalent groups that are connected.In certain embodiments, two cyclohexanol modules comprise 2 divalent groups that are connected.In certain embodiments, the divalent group that is connected is selected from-O-,-S-,-N (R1)-,-C (R1) (R2)-,-C (R1)=C (R1)-,-C (R1)=N-,-C (=NR1)-,-Si (R1) (R2)-,-S (=O) ₂-,-S (=O)-,-C (=O)-and-C (=S)-; Wherein each R1 and R2 are H independently; hydroxyl; C1-C12 chain alkylene/alkyl group; C1-C12 chain alkylene/the alkyl group that replaces; the C2-C12 alkenyl; the C2-C12 alkenyl that replaces; the C2-C12 alkynyl group; the C2-C12 alkynyl group that replaces; the C5-C20 aryl; the C5-C20 aryl that replaces; heterocyclic radical; the heterocyclic radical that replaces; heteroaryl; the heteroaryl that replaces; the C5-C7 alicyclic radical; the C5-C7 alicyclic radical that replaces; halogen; the oxygen that replaces (O-); amino; the amino that replaces; azido-; carboxyl; the carboxyl that replaces; acyl group; the acyl group that replaces; CN; thiol group; the thiol group that replaces; alkylsulfonyl (S (=O) ₂-H), the alkylsulfonyl that replaces, sulfinyl (sulfoxyl) (S (=O)-H) or the sulfinyl that replaces; And each substituting group is the acyl group, C1-C12 ammonia chain alkylene, C1-C12 ammonia chain-oxyl, the C1-C12 ammonia chain alkylene of replacement, the C1-C12 ammonia chain-oxyl or the blocking group of replacement of amino, acyl group, the replacement of C2-C12 alkynyl group, amino, the replacement of C2-C12 alkenyl, C2-C12 alkynyl group, the replacement of C1-C12 chain alkylene/alkyl group, C2-C12 alkenyl, the replacement of halogen, C1-C12 chain alkylene/alkyl group, replacement independently.

In some embodiment, two cyclohexanol modules with the divalent group bridge joint that is selected from down group 2 ' and 4 ' carbon atom between :-O-(CH ₂) p-,-O-CH2-,-O-CH ₂CH ₂-,-O-CH (chain alkylene)-,-NH-(CH ₂) p-,-N (chain alkylene)-(CH ₂) p-,-O-CH (chain alkylene)-,-(CH (chain alkylene))-(CH ₂) p-,-NH-O-(CH ₂) p-,-N (chain alkylene)-O-(CH ₂) p-or-O-N (chain alkylene)-(CH ₂) p-, wherein p be 1,2,3,4 or 5 and each chain alkylene can be further to replace.In certain embodiments, p is 1,2 or 3.

On the one hand, each described bridge be independently-[C (R1) (R2)] n-,-[C (R1) (R2)] n-O-,-C (R1R2)-N (RI)-O-or-C (R1R2)-O-N (R1)-.On the other hand, each described bridge be 4 independently '-(CH ₂) ₃-2 ', 4 '-(CH ₂) ₂-2 ', 4 '-CH ₂-O-2 ', 4 '-(CH ₂) ₂-O-2 ', 4 '-CH ₂-O-N (R1)-2 ' and 4 '-CH ₂-N (R1)-O-2 '-, wherein each R1 is H, blocking group or C1-C12 chain alkylene independently.

Definition

Unless otherwise defined, the meaning of all technology used herein and scientific terminology and common understand identical of one of ordinary skill in the art of the present invention.Unless specific definition is provided, employed about analytical chemistry described herein, synthetic organic chemistry, and medical science and pharmaceutical chemical term and rules and technology be well known in the art and generally use.Standard technique can be used for chemosynthesis, chemical analysis, medication preparation, prepare and send, reaches the treatment to the experimenter.Some this type of technology and rules can find for example " Antisense Drug Technology:Principles, Strategies, and Applications ", Stanley Crooke, Boca Raton:Taylor ﹠amp in following document; Francis Group, 2008; " Carbohydrate Modifications in Antisense Research ", Sangvi and Cook compile, American Chemical Society, Washington D.C., 1994; " Remington ' sPharmaceutical Sciences ", Mack Publishing Co., Easton, Pa., the 18th edition, 1990; And state the document of incorporating this paper into by carrying for any purpose.In situation about allowing, except as otherwise noted, spreading all over all patents, patent application, the application of having announced and open text, GENBANK sequence, website and other material of having announced mentioned in the whole disclosure herein all states integral body and incorporates this paper into by carrying.All

Accession number and their correlated series and belong to the structured data (comprising gene organization and structural element and SNP information) of these sequences can be such as (the National Center for Biotechnology Information of (U.S.) NCBI, NCBI) find in the sequence library, they are all stated integral body and incorporate this paper into by carrying.Term in this article exists in the situation of various definitions, being as the criterion in saving with this.When mentioning URL or other this class identifier or address, will be appreciated that this class identifier can change, and the customizing messages on the Internet can exist or disappear, but can find the information that is equal to by the search Internet.Mention the availability and the open propagation of the such information of their proofs.

" pharmaceutical composition " is meant the mixture that is fit to material that individuality is used.For example, pharmaceutical composition can comprise antisense oligonucleotide and aseptic aqueous solution.

" using " is to point to individuality medicament is provided, and includes but not limited to be used and used voluntarily by the medical matters professional.

" individuality " is meant selected receiving treatment or the people of therapy or inhuman animal.

" extended period " is meant the time period that activity or incident continue.In certain embodiments, the extended period of treatment is the time period of using drug dose betwixt.

" parenteral is used " is meant by injection or perfusion and uses.Parenteral is used and is included but not limited to that subcutaneous administration, intravenously are used or intramuscular is used.

" subcutaneous administration " is meant using below skin." intravenously is used " is meant and enters using of vein.

" agent (amount) " (dose) is meant the specified amount of the medicament that single administration provides.In certain embodiments, potion can be injected agent (boluses), tablet or injection by two or more and used.For example, in certain embodiments, when the needs subcutaneous administration, the volume that the dosage that needs requires single injection to be not easy to realize.In such embodiments, twice or more times injection can be used for obtaining the dosage that needs.In certain embodiments, potion can be used so that individual injection site reaction minimizes by twice or more times injection.

" dosage device " (dosage unit) is meant the form that medicament is provided.In certain embodiments, dosage device is the phial that freeze dried antisense oligonucleotide is housed.In certain embodiments, dosage device is the phial that the antisense oligonucleotide of reconstruction is housed.

" medicament " provides the material of treatment benefit when being meant individuality being used.For example, in certain embodiments, the antisense oligonucleotide of target PCSK9 is a medicament.

" thinner " is meant the composition that does not have pharmaceutical activity in the composition, but is essential or expectation in pharmacy.For example, in injectable drug, thinner can be liquid, for example salt brine solution.

" active pharmaceutical ingredient " is meant the material that desired effects is provided in the pharmaceutical composition.

" pharmaceutical acceptable carrier " is meant medium or the thinner that does not disturb oligonucleotide structure.Some this class carrier makes pharmaceutical composition for example can be mixed with tablet, pill, dragee (dragee), capsule, liquid, gel, syrup, slurry, suspension and lozenge (lozenge) by experimenter's orally ingestible.

" treatment significant quantity " is meant the pharmaceutical quantities that individuality is provided the treatment benefit.In certain embodiments, the treatment significant quantity of the antisense compounds of target PCSK9 nucleic acid is to reduce the amount of LDL-C in the individuality.

" hypercholesterolemia " is meant that the serum cholesterol to raise is the situation of feature.

" hyperlipidaemia " is meant that the serum lipid to raise is the situation of feature.

" HTC " is meant that the triglyceride level to raise is the situation of feature.

" non-familial hypercholesterolemia " be meant be not to cause by term single gene sudden change, be the situation of feature with the cholesterol that raises.

" polygenic hypercholesterolemia " be meant cause by multiple genic influence, be the situation of feature with the cholesterol that raises.In certain embodiments, polygenic hypercholesterolemia may be taken in lipid because of diet and worsens.

The autosomal dominant metabolic disorder that " familial hypercholesterolemia (FH) " is meant with the sudden change in ldl receptor (LDL-R) gene, the LDL-C that significantly raises and atherosclerotic too early outbreak is feature.When individuality meets one of following standard or it can be diagnosed as familial hypercholesterolemia when multinomial: the ldl receptor gene of 2 sudden changes is confirmed in the heredity test; The ldl receptor gene of a sudden change is confirmed in the heredity test; Untreated serum LDL-cholesterol is higher than the medical history of 500mg/dL; The tendon before 10 years old and/or the xanthoma of skin; Or the serum LDL-cholesterol of parents' rising that coincide with the heterozygosity familial hypercholesterolemia that record all arranged before the lipopenicillinase therapy.

" HFH " or " HoFH " is meant that the two all has the situation of the feature of sporting with parent and male parent LDL-R gene.

" heterozygosity familial hypercholesterolemia " or " HoFH " are meant with parent or the two arbitrary situation that the feature of sporting is arranged of male parent LDL-R gene.

" mixed type dyslipidemia " is meant that with the serum cholesterol that raises and the S-TG of rising be the situation of feature.

" diabetes dyslipidemia (diabetic dyslipidemia) " or " with the type ii diabetes (Type II diabetes with dyslipidemia) of dyslipidemia " is meant the situation that the little fine and close LDL particle of the S-TG of HDL-C with type ii diabetes, reduction, rising and rising is a feature.

Danger diseases (CHD risk equivalents) such as " " coronary heart disease is meant that there is the indication of the clinical arteriosclerosis disease of high coronary heart disease risk in expression, and comprises clinical crown worry, symptomatic carotid disease, peripheral arterial disease and/or abdominal aortic aneurysm.

" metabolic syndrome (metabolic syndrome) " is meant that bunch collection (clustering) to be derived from the metabolic lipid and the non-lipid cardiovascular risk factor is the situation of feature.In certain embodiments, identify metabolism syndrome by appearance any 3 in the following factor: the male sex is greater than 102cm and the women waistline greater than 88cm; At least the S-TG of 150mg/dL; The male sex is less than 40mg/dL and the women HDL-C less than 50mg/dL; At least the blood pressure of 130/85mmHg; At least the fasting glucose of 110mg/dL.

" non-alcoholic fatty liver disease (non-alcoholic fatty liver disease) (NAFLD) " is meant not use liver fat inflammation that (for example the alcohol consumption amount was above 20g/ days) the cause situation as feature because of excessive alcohol.In certain embodiments, NAFLD is relevant with insulin resistant and metabolic syndrome.

" nonalcoholic fatty liver disease (non-alcoholic steatohepatitis) (NASH) " is meant that the accumulation with the inflammation in the liver and fat and fibrous tissue is a feature, but not because excessive alcohol uses the situation that causes.NASH is the extreme form of NAFLD.

" the principal risk factor (major risk factors) " is meant the contributive factor of the excessive risk of coronary heart disease, includes but not limited to smoking, hypertension, low HDL-C, familial history of coronary artery disease and age.

" the coronary heart disease risk factor " is meant the danger disease and the principal risk factors such as coronary heart disease.

" coronary heart disease (CHD) " is meant that the little blood vessel for heart supply blood and oxygen narrows down, and it usually is atherosclerotic result.

" coronary heart disease risk of reduction " is meant that a possibility of knowing from experience generation coronary heart disease reduces.In certain embodiments, the reduction of coronary heart disease risk is to measure for example reduction of LDL-C level by the improvement of or the multinomial coronary heart disease risk factor.

" atherosclerosis (atherosclerosis) " is meant the artery hardening of the large-scale and medium-sized artery of influence and with the feature that appears as of fatty deposits.Described fatty deposits is called " congee sample spot (atheroma) " or " patch (plaque) ", and it is mainly formed and damaged the lining (lining) of artery by cholesterol and other fat, calcium and scar tissue.

" coronary disease medical history (history of coronary heart disease) " is meant the significantly appearance of coronary heart disease clinically in individuality or individual family member's medical history.

" early tuinga worry (early onset coronary heart disease) " is meant making a definite diagnosis of coronary heart disease before 50 years old.

" individuality that his spit of fland does not tolerate (statin intolerant individual) " is meant the result as his statin therapy, and the experience creatine kinase increases, liver functional test is unusual, one or multinomial individuality in myalgia or the central nervous system side effect.

" effect/effectiveness (efficacy) " is meant the ability that produces desired effects.The effectiveness of for example, lipopenicillinase therapy can be the reduction of one or more concentration in LDL-C, VLDL-C, IDL-C, non-HDL-C, ApoB, lipoprotein (a) or the tri-glyceride.

" acceptable safety spectrum (acceptable safety profile) " is meant the pattern that can accept the side effect in the limit clinically.

" side effect " is meant the physiological responses except that the effect of expectation that is caused by treatment.In certain embodiments, side effect includes but not limited to that injection site reaction, liver functional test are unusual, renal function dysfunction, liver poisoning, nephrotoxicity, central nervous system is unusual and myopathy.For example, the transaminase level that raises in the serum can be indicated liver poisoning or dysfunction of liver.For example, the bilirubin of rising can be indicated liver poisoning or dysfunction of liver.

" injection site reaction (injection site reaction) " is meant place, injection site chafing or rubescent unusually in the individuality.

" individuality is deferred to (individual compliance) " is meant individual observing therapy that recommend or the prescription regulation.

" lipopenicillinase therapy (lipid-lowering therapy) " is meant the treatment plan that offers one or more lipids in the individual reduction individuality.In certain embodiments, provide the lipopenicillinase therapy to reduce among ApoB in the individuality, total cholesterol, LDL-C, VLDL-C, IDL-C, non-HDL-C, tri-glyceride, little fine and close LDL particle and the Lp (a) one or multinomial.

" lipid lowering agent (lipid-lowering agent) " is meant and offers individual medicament to realize that lipid reduces in the individuality.For example, in certain embodiments, for individuality provides lipid lowering agent with one in reduction ApoB, LDL-C, total cholesterol and the tri-glyceride or multinomial.

" LDL-C target (LDL-C target) " is meant the LDL-C level of expecting after the lipopenicillinase therapy.

" defer to " and be meant individual observing the therapy of recommending.

" therapy of recommendation " be meant by the medical matters professional and recommend, and is used for the treatment of, improvement or prophylactic treatment plan.

" low ldl receptor activity (low LDL-receptor activity) " is meant the ldl receptor activity of the clinical acceptable level that is not high enough to keep LDL-C in the blood flow.

" cardiovascular consequence (cardiovascular outcome) " is meant the generation of great unfavorable cardiovascular event.

" the cardiovascular consequence of improvement " is meant that great unfavorable cardiovascular event takes place or the minimizing of its risk.The example of great unfavorable cardiovascular event includes but not limited to death, infraction, apoplexy, cardiogenic shock, pulmonary edema, asystole and atrium dysrhythmia again.

" the surrogate markers thing of cardiovascular consequence (surrogate markers of cardiovascular outcome) " is meant the indirect indicator of cardiovascular event or its risk.For example, the surrogate markers thing of cardiovascular consequence comprises carotid artery intima middle level thickness (CIMT).Another example of the surrogate markers thing of cardiovascular consequence comprises congee sample spot size.Congee sample spot size can be measured by intravascular ultrasound (IVUS).

" HDL-C of rising (increased HDL-C) " is meant individual Serum HDL-C rising in time.

" lipopenicillinase (lipid-lowering) " is meant individual one or more serum lipid minimizing in time.

" use altogether " and be meant individuality is used two or more medicaments.Two or more medicaments can be in single pharmaceutical compositions or can be in the separated drug compositions.In two or more medicaments each can be used by identical or different route of administration.Use altogether and comprise parallel or sequential using.

" concomitant administration (administered concomitantly) " be meant with two kinds of agent with identical treatment time framework (time frame) so that any way that the pharmacotoxicological effect of two kinds of agent occurs in the patient simultaneously use.Concomitant administration does not require two kinds of agent in single pharmaceutical composition, use with identical dosage form or by identical route of administration.

" change of therapeutic mode of life " is meant that being intended to reducing cholesterol suffers from the diet of cardiopathic risk and the change of mode of life with reducing, and comprise total heat every day of recommended dietary picked-up, total fat, saturated fatty, polyunsaturated fat, single unsaturated fatty acids, sugar, protein, cholesterol, insoluble fibre, and recommend sports.

" his spit of fland/statin (statin) " is meant the medicament that suppresses the HMG-CoA reductase activity.

" HMG-CoA reductase inhibitor " is meant by suppressing the medicament that HMG-CoA reductase enzyme this kind of enzyme plays a role.

" cholesterol absorption inhibitor (cholesterol absorption inhibitor) " is meant the medicament that suppresses to absorb from the external source cholesterol of diet acquisition.

" LDL removes (LDL apheresis) " is meant a kind of (blood part composition) removing form that LDL-C is removed from blood.Usually, take out individual blood from vein, and be separated into red corpuscle and blood plasma.Before blood plasma and red corpuscle are returned individuality, LDL-C is filtered out from blood plasma.

" MTP inhibitor " is meant the medicament that suppresses microsome tri-glyceride transfer protein this kind of enzyme.

" LDL-C (LDL-C) " is meant the cholesterol of carrying in the low-density lipoprotein particle.The concentration of LDL-C is quantitative with mg/dL or nmol/L usually in the serum (or blood plasma)." serum LDL-C " and " blood plasma LDL-C " refers to the LDL-C in serum and the blood plasma respectively.

" vldl-cholesterol (VLDL-C) " is meant and vldl particle bonded cholesterol.The concentration of VLDL-C is quantitative with mg/dL or nmol/L usually in the serum (or blood plasma)." serum VLDL-C " and " blood plasma VLDL-C " refers to the VLDL-C in serum or the blood plasma respectively.

" intermediate low density lipoprotein-cholesterol (IDL-C) " is meant and intermediate density lipoprotein bonded cholesterol.The concentration of IDL-C is quantitative with mg/mL or nmol/L usually in the serum (or blood plasma)." serum I DL-C " and " blood plasma IDL-C " refers to the IDL-C in serum or the blood plasma respectively.

" NHDL-cholesterol (non-HDL-C) " is meant and the lipoprotein bonded cholesterol except that high-density lipoprotein (HDL), includes but not limited to LDL-C, VLDL-C and IDL-C.

" high-density lipoprotein (HDL)-C (HDL-C) " is meant and high-density lipoprotein (HDL) particle bonded cholesterol.The concentration of HDL-C is quantitative with mg/dL or nmol/L usually in the serum (or blood plasma)." Serum HDL-C " and " blood plasma HDL-C " refers to the HDL-C in serum and the blood plasma respectively.

" total cholesterol " is meant all types of cholesterol, includes but not limited to LDL-C, HDL-C, IDL-C and VLDL-C.The concentration of total cholesterol is quantitative with mg/dL or nmol/L usually in the serum (or blood plasma).

" lipoprotein (a) " or " Lp (a) " is meant the hdl particle that is made of LDL-C, lipophorin (a) particle and Apolipoprotein B-100 particle.

" ApoA1 " is meant the lipophorin-A1 albumen in the serum.ApoA1 concentration in the serum is quantitative with mg/dL or nmol/L usually.

" ApoB: ApoA1 ratio " is meant the ratio of ApoB concentration and ApoA1 concentration.

" lipoprotein that contains ApoB " is meant and contains any lipoprotein of apolipoprotein B as its protein component, and be understood to include LDL, VLDL, IDL and lipoprotein (a).

" little LDL particle " is meant subclass of LDL particulate, it is characterized in that comparing littler, finer and close size with other LDL particle.In certain embodiments, medium LDL particle diameter is 23-27nm.In certain embodiments, big LDL particle diameter is 21.2-23nm.In certain embodiments, little LDL particle diameter is 18-21.2nm.In certain embodiments, granular size is measured by nuclear magnetic resonance spectroscopy.

" little VLDL particle " is meant subclass of VLDL particulate, it is characterized in that comparing littler, finer and close size with other VLDL particle.In certain embodiments, big VLDL particle diameter is greater than 60nm.In certain embodiments, medium VLDL particle diameter is 35-60nm.In certain embodiments, little VLDL particle diameter is 27-35nm.In certain embodiments, granular size is measured by nuclear magnetic resonance spectroscopy.

" tri-glyceride " is meant the lipid as three esters of glycerine." S-TG " is meant the tri-glyceride that exists in the serum." liver tri-glyceride " is meant the tri-glyceride that exists in the hepatic tissue.

" serum lipid " is meant cholesterol and the tri-glyceride in the serum.

" total cholesterol of rising " is meant that the total cholesterol in the individuality is in the concentration of recommending the lipopenicillinase therapy, includes but not limited to " LDL-C of rising ", " VLDL-C of rising ", " IDL-C of rising " and " the non-HDL-C of rising ".In certain embodiments, the total cholesterol concentration that is lower than 200mg/dL, 200-239mg/dL and is higher than 240mg/dL is considered to ideal, critical higher (borderline high) and high respectively.In certain embodiments, 100mg/dL, 100-129mg/dL, 130-159mg/dL, 160-189mg/dL and greater than the LDL-C concentration of 190mg/dL be considered to best respectively, be close to best/be higher than best, critical higher, high with high.

" tri-glyceride of rising " is meant that the tri-glyceride in serum or the liver is in the concentration of recommending the lipopenicillinase therapy, comprises " S-TG of rising " and " the liver tri-glyceride of rising ".In certain embodiments, 150-199mg/dL, 200-499mg/dL and be considered to critical higher, high respectively with high more than or equal to the S-TG concentration of 500mg/dL.

" the little LDL particle of rising " is meant that the little LDL particle in the individuality is in the concentration of recommending the lipopenicillinase therapy.

" the little VLDL particle of rising " is meant that the little VLDL particle in the individuality is in the concentration of recommending the lipopenicillinase therapy.

" lipoprotein of rising (a) " is meant that the lipoprotein (a) in the individuality is in the concentration of recommending the lipopenicillinase therapy.

" low HDL-C " is meant that the HDL-C in the individuality is in the concentration of recommending the lipopenicillinase therapy.In certain embodiments, as low HDL-C during, recommend the lipopenicillinase therapy with the rising of the rising of non-HDL-C and/or tri-glyceride.In certain embodiments, think that the HDL-C concentration less than 40mg/dL is low.In certain embodiments, think that the HDL-C concentration less than 50mg/dL is low.

" ApoB " is meant Apolipoprotein B-100 albumen.ApoB concentration in the serum (or blood plasma) is quantitative with mg/dL or nmol/L usually." serum ApoB " and " plasma A poB " refer to the ApoB in serum and the blood plasma respectively.

" LDL/HDL ratio " is meant the ratio of LDL-C to HDL-C.

" LDL of oxidation " or " Ox-LDL-C " are meant LDL-C oxidized after being exposed to free radical.

" LDL-C level raise individuality " is meant to be accredited as according to the governing principle of medical matters professional approval by medical matters professional (for example physician) to have the individuality that is close to or higher than the LDL-C level of recommending to carry out therapeutic intervention.Such individuality also may be considered to " needing treatment " to reduce the LDL-C level.

" apoB-100 level raise individuality " is meant to be accredited as according to the governing principle of medical matters professional approval by medical matters professional (for example physician) to have the individuality that is close to or higher than the apoB-100 level of recommending to carry out therapeutic intervention.Such individuality also can be considered to " needing treatment " to reduce the apoB-100 level.

" the LDL-C level that treatment raises " is meant the antisense compounds of the individuality of LDL-C level rising being used target PCSK9 nucleic acid.

" treatment atherosclerosis " is meant the antisense compounds of individuality being used target PCSK9 nucleic acid, and described individuality suffers from based on doctor's assessment or might suffer from atherosclerosis." prevention of arterial is atherosis " is meant the antisense compounds of individuality being used target PCSK9 nucleic acid, described individuality based on doctor's assessment to the atherosclerosis susceptible.

" target nucleic acid ", " target RNA ", " target rna transcription thing " and " nucleic acid target " all is meant can be by any nucleic acid of antisense compounds target.

" PCSK9 nucleic acid " is meant any nucleic acid of coding PCSK9.For example, in certain embodiments, PCSK9 nucleic acid include but not limited to encode PCSK9 dna sequence dna, transcribe the RNA sequence that obtains and the mRNA sequence of coding PCSK9 from the DNA of coding PCSK9." PCSK9mRNA " is meant the proteic mRNA of coding PCSK9.

" target (targeting) " is meant design and the chosen process that can hybridize and induce the antisense compounds of expectancy effect specifically with target nucleic acid.

" target/fixed (targeted) of target " be meant to have following nuclear base sequence, it can allow antisense compounds and target nucleic acid specific hybrid to induce expectancy effect.In certain embodiments, expectancy effect is the minimizing of target nucleic acid.In some such embodiment, expectancy effect is the minimizing of PCSK9mRNA.

The target nucleic acid level of target nucleic acid level when " Antisense Suppression " is meant existence with target nucleic acid complementary antisense compounds when not having described antisense compounds compared reduction.

" target area " is meant the fragment of one or more antisense compounds institute targets in the target nucleic acid.

" target area section " is meant the nucleotide sequence of antisense compounds institute target in the target nucleic acid." 5 ' target site " is meant the 5 ' terminal nucleotide of target area section." 3 ' target site " is meant the 3 ' terminal nucleotide of target area section.

" active target area " is meant the target area of one or more active antisense compounds institute targets." active antisense compounds " is meant the antisense compounds that reduces the target nucleic acid level.

" hybridization " is meant the annealing of complementary nucleic acid molecule.In certain embodiments, complementary nucleic acid molecule includes but not limited to antisense compounds and nucleic acid target.In some such embodiment, complementary nucleic acid molecule includes but not limited to antisense oligonucleotide and nucleic acid target.

" tight hybridization conditions " is meant such condition, and nucleic acid molecule under this condition (such as antisense compounds) can be hybridized with target nucleic acid sequence, but considerably less with other sequence hybridization.

" hybridization specifically " is meant that antisense compounds and target nucleic acid hybridization to induce expectancy effect, represent minimal effect or do not have effect non-target nucleic acid simultaneously.

" complementarity " is meant the pairing ability between the nuclear base of first nucleic acid and second nucleic acid.

" fully complementary " be meant first nucleic acid each nuclear base can with each nuclear base pairing of second nucleic acid.In certain embodiments, first nucleic acid is antisense compounds, and target nucleic acid is second nucleic acid.In some such embodiment, antisense oligonucleotide is first nucleic acid, and target nucleic acid is second nucleic acid.

" incomplementarity nuclear base " be meant in first nucleic acid can not with the nuclear base of the corresponding nuclear base pairing of target nucleic acid." mispairing " be meant first nucleic acid the nuclear base can not with the corresponding nuclear base pairing of target nucleic acid.

" partly (portion) " is meant successive (promptly being connected) the nuclear base of restricted number in the target nucleic acid.In certain embodiments, part is the continuous kernel base of restricted number in the target nucleic acid.In certain embodiments, part is the continuous kernel base of restricted number in the antisense compounds.

" oligomeric compounds " be meant can with the polymkeric substance of the monomer subunit that is connected of an area hybridization of RNA molecule at least.

" antisense compounds " is meant can be by the oligomeric compounds of hydrogen bonding generation with the hybridization of target nucleic acid.

" oligonucleotide " is meant the polymkeric substance of the nucleosides that is connected, wherein each nucleosides can be independently of one another modify or unmodified.

" oligonucleoside " is meant and wherein connects the oligonucleotide that does not contain phosphorus atom between nucleosides.

" Nucleotide of unmodified " is meant the Nucleotide that connects and composes by between naturally occurring nuclear base, sugared module and nucleosides.In certain embodiments, the Nucleotide of unmodified is RNA Nucleotide (being β-D-ribonucleoside) or DNA Nucleotide (being β-D-dezyribonucleoside).

" antisense oligonucleotide " is meant the oligonucleotide of strand, and it has, and meeting allows and the nuclear base sequence of the respective regions hybridization of target nucleic acid.

" motif " is meant unmodified in the antisense compounds and the pattern nucleosides of modifying.

" chimeric antisense compounds " is meant the antisense compounds with at least 2 chemical difference region, and each zone has a plurality of subunits." breach polymers (gapmer) " is meant such antisense compounds, wherein interior location is between the external region, described interior location has a plurality of Nucleotide of supporting RNA enzyme H cutting, and described external region has one or more Nucleotide at the nucleosides that chemically differs from interior region." breach section " is meant a plurality of Nucleotide that constitute breach polymers interior region." pterion section " is meant the external region of breach polymers.

" breach is widened " is meant such antisense compounds, and it has 12 or the breach section of more a plurality of successive 2 '-deoxyribonucleotide that is positioned between 5 ' and 3 ' the pterion section, and described pterion section has 1-6 Nucleotide that contains the sugared module of modification.

" nucleosides " is meant the nuclear base that is connected with sugar.

" nuclear base " be meant can with the heterocyclic base module of the base pairing of another nucleic acid.

" Nucleotide " is meant the nucleosides with covalently bound phosphate group to the nucleosides sugar moieties.

" nuclear base sequence " is meant the continuous kernel base order that is independent of any sugar, connection and/or nuclear base modification.

" Nucleotide of modification " is meant the Nucleotide of the nuclear base that connects between the nucleosides of the sugared module that has modification independently, modification or modify.

" nucleosides of modification " is meant the Nucleotide of the nuclear base of the sugared module that has modification independently or modification.

" successive nuclear base " is meant nuclear base adjacent one another are.

" Nucleotide of modification " is meant between the nucleosides that comprises modification the oligonucleotide of sugar that connects, modifies and/or the nuclear base of modifying.

" oligonucleotide of the modification of strand " is meant not the oligonucleotide with the modification of complementary strand hybridization.

" connect " chemical bond that is meant between the nucleosides between nucleosides.

" nucleosides that is connected " is meant the adjacent nucleosides that is bonded together.

" deoxynucleoside that is connected " be meant nucleic acid base (A, G, C, T U) is replaced to form Nucleotide by the ribodesose that is connected by phosphoric acid ester.

" connect between naturally occurring nucleosides " be meant 3 ' to 5 ' phosphodiester connect.

" connect " replacement and/or any variation that are meant with respect to key between naturally occurring nucleosides between the nucleosides of modification.In some cases, connection refers to key between the phosphodiester nucleosides between the nucleosides of modification.

" thiophosphatephosphorothioate connection " is meant between the following nucleosides and connects, wherein modify phosphodiester bond by replace one of non-bridge joint Sauerstoffatom with sulphur atom.It is to connect between the nucleosides of modifying that thiophosphatephosphorothioate connects.

" the sugared module of modification " is meant replacement and/or any variation with respect to the natural sugar module.With regard to the disclosure, " natural sugar module " is at DNA (2 '-H) or RNA (the sugared module that finds in 2 '-OH).

" sugar of modification " is meant with respect to the replacement of natural sugar and/or any variation.

" dicyclo sugar " is meant the furan nucleus of modifying by two non-one-tenth dicyclo atoms of bridge joint (furosyl ring).Dicyclo sugar is the sugar of modifying.

" the nuclear base of modification " is meant any nuclear base outside VITAMIN B4, cytosine(Cyt), guanine, thymus pyrimidine or the uridylic." the nuclear base of unmodified " is meant purine base adenine (A) and guanine (G), pyrimidine bases thymus pyrimidine (T), cytosine(Cyt) (C) and uridylic (U).

" the sugared module of modification " is meant the sugared module that has with respect to replacement and/or any variation of natural sugar module.

" natural sugar module " is meant at DNA (2 '-H) or RNA (the sugared module that finds in 2 '-OH).

" 2 '-O-methoxyethyl sugar module " be meant have 2 '-O (CH2) ₂-OCH ₃(the furan nucleus of 2 '-O-methoxyethyl or 2 '-MOE) substituent 2 '-replacement.

" 2 '-O-methoxyethyl Nucleotide " is meant the Nucleotide of the sugared module that comprises the modification of 2 '-O-methoxyethyl.

" 2 '-O-methoxyethyl " is meant the O-methoxyl group-ethyl modification to furan nucleus 2 ' position.The sugar that 2 '-O-methoxyethyl is modified is the sugar of modifying.

" dicyclo ribose module " is meant the furan nucleus of modifying by two non-one-tenth dicyclo atoms of bridge joint.

" 5-methylcytosine " is meant the cytosine(Cyt) of modifying with the methyl that is attached to 5 ' position.5-methylcytosine is the nuclear base of modifying.

" prodrug (prodrug) " is meant that its effect by endogenous enzyme or other chemical substance and/or condition in body or in the cell of body changes into activity form (being medicine) with the therapeutical agent of inactive form preparation.

" pharmacologically acceptable salts " is meant the salt of acceptable antisense compounds on physiology and the pharmacology, promptly kept the expectation biologic activity of parent's oligonucleotide and do not given the salt of its toxicological effect of not expecting.

" salt " is meant the salt of acceptable antisense compounds on physiology and the pharmacology, has promptly kept the expectation biologic activity of parent's oligonucleotide and has not given the salt of its toxicological effect of not expecting.

" cure (cures) " is meant restorative method or process, or the prescription regulation to treatment of diseases.

" slow down progress " and be meant that described advancing of disease reduces.

" cap structure " or " distal end cap module " is meant the chemically modified of the arbitrary end that is impregnated in antisense compounds.

" ISIS 301012 " are meant a kind of lipid lowering agent, it is a kind of antisense oligonucleotide with sequence " GCCTCAGTCTGCTTCGCACC " (SEQ ID NO:457), wherein connect between each nucleosides is that thiophosphatephosphorothioate connects, each cytosine(Cyt) is a 5-methylcytosine, Nucleotide 6-15 is 2 '-deoxynucleotide, and Nucleotide 1-5 and 16-20 are 2 '-O-methoxyethyl Nucleotide.

General view

LDL-cholesterol (HDL-C) level that raises is construed to the main independent risks and assumptions of coronary heart disease (CHD).Even through benefit from aggressiveness treatment that present available cholesterol-lowering agent carries out with the individuality that reduces LDL-cholesterol (LDL-C) level in, coronary artery events is still taking place, and the LDL-C level that raises remains the principal risk factor of coronary heart disease in these individualities.In addition, many target LDL-C levels that do not reaching them through the individuality of the LDL therapy of accepting a surrender, therefore and the risk of CHD is still arranged.Thereby, need other to fall the LDL-C agent.

Antisense compounds that is provided and method are useful for the treatment hypercholesterolemia herein.The treatment of hypercholesterolemia comprises the treatment plan that produces clinical expected result.For example, antisense compounds that is provided and method are useful for the cholesterol of treatment rising such as the LDL-C that raises herein.In addition, antisense compounds that is provided herein and method are used in and reduce the CHD risk in the individuality that shows one or more CHD risks and assumptions.In addition, antisense compounds that is provided herein and method can be used for treating and/or preventing atherosclerosis.

Illustrated as this paper, antisense oligonucleotide from target PCSK9 to the animal (experimental model of hyperlipidaemia) of feed high fat diet that use has caused the Antisense Suppression to PCSK9, the rise of LDL-R, the reduction of LDL-C level and the reduction of liver tri-glyceride.So, proved in the experimental model of hyperlipidaemia, caused the LDL-C level to reduce the Antisense Suppression of PCSK9.Thereby, providing the method that is used for the treatment of herein, it reduces the LDL-C level by the antisense compounds of using target PCSK9 nucleic acid.The LDL-C level that raises is considered to the risks and assumptions of CHD, and also relevant with atherosclerosis.Thereby, also provide herein to be used to reduce the method for CHD risk and to be used to prevent and/or treat atherosclerotic method.It is the method for the situation (such as fatty degeneration of liver) of feature that the liver tri-glyceride that is used for the treatment of to raise also is provided herein.

Some indication

In certain embodiments, the invention provides the individual method of treatment, comprise and use one or more pharmaceutical compositions of the present invention.In certain embodiments, described individuality has hypercholesterolemia (hypercholesterolemia), mixed type dyslipidemia (mixed dyslipidemia), atherosclerosis (atherosclerosis), incidence of atherosclerosis risk (a risk ofdeveloping atherosclerosis), coronary heart disease (coronary heart disease), coronary disease medical history (a history of coronary heart disease), tuinga worry (early onset coronary heart disease) early, acute coronary syndrome (acutecoronary syndrome), one or more coronary heart disease risk factors (one or more risk factors forcoronary heart disease), type ii diabetes (type II diabetes), type ii diabetes (type II diabetes with dyslipidemia) with dyslipidemia, dyslipidemia (dyslipidemia), HTC (hypertriglyceridemia), hyperlipidaemia (hyperlipidemia), high fatty acid mass formed by blood stasis (hyperfattyacidemia), fatty degeneration of liver (hepatic steatosis), nonalcoholic fatty liver disease (non-alcoholic steatohepatitis), or non-alcoholic fatty liver disease (non-alcoholic fatty liverdisease).

The guide of lipopenicillinase therapy is by NCEP (National CholesterolEducation Program, NCEP)) the III of adult treatment expert group (Adult Treatment Panel III, ATP III) sets up in calendar year 2001, and in renewal (Grundy et al. in 2004, Circulation, 2004,110,227-239).This guide comprises that obtaining complete lipoprotein composes, and normally after 9 to 12 hours fasting, is used for determining LDL-C, total cholesterol and HDL-C level.According to the guide of nearest foundation, the horizontal 130-159mg/dL of LDL-C, 160-189mg/dL and be considered to critical high level, high level and high level respectively more than or equal to 190mg/dL.Total cholesterol level 200-239mg/dL and be considered to critical high level and high level respectively more than or equal to 240mg/dL.The HDL-C level is lower than 40mg/dL and is considered to low-level.

In certain embodiments, described individuality has been accredited as and need have accepted the lipopenicillinase therapy.In some such embodiment, described individuality has been accredited as need to be accepted to set up in calendar year 2001 according to the III of adult treatment expert group (ATP III) of NCEP (NCEP), and in renewal (Grundy et al. in 2004, Circulation, 2004,110, the lipopenicillinase therapy that guide 227-239) carries out.In some such embodiment, the LDL-C that need accept the individuality of lipopenicillinase therapy is higher than 190mg/dL.In some such embodiment, the LDL-C that need accept the individuality of lipopenicillinase therapy is higher than 160mg/dL.In some such embodiment, the LDL-C that need accept the individuality of lipopenicillinase therapy is higher than 130mg/dL.In some such embodiment, the LDL-C that need accept the individuality of lipopenicillinase therapy is higher than 100mg/dL.In some such embodiment, the individuality that need accept the lipopenicillinase therapy should be kept LDL-C and be lower than 160mg/dL.In some such embodiment, the individuality that need accept the lipopenicillinase therapy should be kept LDL-C and be lower than 130mg/dL.In some such embodiment, the individuality that need accept the lipopenicillinase therapy should be kept LDL-C and be lower than 100mg/dL.In some such embodiment, described individuality should be kept LDL-C and be lower than 70mg/dL or even be lower than 50mg/dL.

In certain embodiments, the invention provides the method for the ApoB that is used for reducing individuality.In certain embodiments, the invention provides the method for the lipoprotein that contains ApoB that is used for reducing individuality.In certain embodiments, the invention provides the method for the LDL-C that is used for reducing individuality.In certain embodiments, the invention provides the method for the VLDL-C that is used for reducing individuality.In certain embodiments, the invention provides the method for the IDL-C that is used for reducing individuality.In certain embodiments, the invention provides the method for the non-HDL-C that is used for reducing individuality.The invention provides the method for the Lp (a) that is used for reducing individuality in certain embodiments.In certain embodiments, the invention provides the method for the S-TG (triglyceride) that is used for reducing individuality.In certain embodiments, the invention provides the method for the liver tri-glyceride that is used for reducing individuality.In certain embodiments, the invention provides the method for the Ox-LDL-C that is used for reducing individuality.In certain embodiments, the invention provides the method for the little LDL particle (small LDL particles) that is used for reducing individuality.In certain embodiments, the invention provides the method for the little VLDL particle (small VLDL particles) that is used for reducing individuality.In certain embodiments, the invention provides the method for the phosphatide that is used for reducing individuality.In certain embodiments, the invention provides the method for the oxidized phospholipids that is used for reducing individuality.

In certain embodiments, method provided by the invention does not reduce HDL-C.In certain embodiments, method provided by the invention does not cause that lipid gathers in the liver.

In one embodiment, be provided for reducing the method for LDL-C level, perhaps be used for the treatment of the method for hypercholesterolemia, described method is by the antisense compounds to the target PCSK9 nucleic acid of suffering from the individual administering therapeutic significant quantity that the LDL-C level raises.In another embodiment, the method that reduces the LDL-C level comprises that selection need reduce the individuality of LDL-C level, and gives the antisense compounds of the target PCSK9 nucleic acid of this individuality administering therapeutic significant quantity.In another embodiment, the method that reduces coronary heart disease risk comprises that selection has the individuality of LDL-C level and one or more other coronary heart disease risk indexs of rising, and gives the antisense compounds of the target PCSK9 nucleic acid of described individual administering therapeutic significant quantity.

In other embodiments, the LDL-C level is 100-129mg/dL, 130-159mg/dL, 160-189mg/dL or more than or equal to 90mg/dL.

In one embodiment, the antisense compounds of the target PCSK9 nucleic acid of treatment significant quantity use the monitoring that is accompanied by LDL-C level in the individual serum, to determine the individual response that described antisense compounds is used.The physician utilizes individual amount and the time length of the response of using described antisense compounds being determined the treatment intervention.

In one embodiment, using of the antisense compounds of target PCSK9 nucleic acid causes the LDL-C level to be lower than 190mg/dL, is lower than 160mg/dL, is lower than 130mg/dL, is lower than 100mg/dL, is lower than 70mg/dL, or is lower than 50mg/dL.In another embodiment, using of the antisense compounds of target PCSK9 nucleic acid makes LDL-C be reduced by at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

The individuality that the LDL-C level rises also can show the HDL-C level of reduction and/or the total cholesterol level of rising.Thereby, in one embodiment, give the antisense compounds of the target PCSK9 nucleic acid of the individual administering therapeutic significant quantity that the LDL-C level rises, described individuality also has the HDL-C level of reduction and/or the total cholesterol level of rising.

The individuality that the LDL-C level rises also can show the triglyceride level of rising.Thereby, in one embodiment, rise the antisense compounds of the target PCSK9 nucleic acid of the individual administering therapeutic significant quantity that triglyceride level also rises for the LDL-C level.

Atherosclerosis can cause coronary heart disease, apoplexy or peripheral vascular disease.The LDL-C level that rises is considered to the risks and assumptions in incidence of atherosclerosis and the progress.Thereby, in one embodiment, give the antisense compounds of the target PCSK9 nucleic acid of suffering from atherosclerotic individual administering therapeutic significant quantity.In a further embodiment, give antisense compounds to the target PCSK9 nucleic acid of the individual administering therapeutic significant quantity of atherosclerosis susceptible.By the imaging technique of routine,, come atherosclerosis is directly assessed such as the ultrasonic imaging technique that for example discloses carotid artery intima middle level thickness.Thereby atherosclerosis therapy and/or prevention also comprise by conventional imaging technique monitoring atherosclerosis.In one embodiment, the antisense compounds of target PCSK9 nucleic acid use the reduction that causes atherosclerosis seriousness, show as, for example, carotid artery intima middle level thickness reduces in the artery.

The observed value that uses individual certainly serum of collecting or blood plasma to obtain cholesterol, lipoprotein and tri-glyceride.The method that obtains serum or plasma sample is conventional, and the method that preparation is used to analyze the serum sample of cholesterol, tri-glyceride and other blood serum designated object also is conventional.

Reduce under the situation of therapy at needs enthusiasm LDL in various degree, the physician can determine individual needs to therapeutic intervention.The enforcement of method herein provides applicable to NCEP, perhaps by other for the physician treats any disease as herein described and illness set up the guide of any modification that main body provided of guide, be used for determining coronary heart disease risk and diagnosis metabolism syndrome.

In one embodiment, using of the antisense compounds of target PCSK9 nucleic acid is that parenteral is used.It can be that intravenously is used or subcutaneous administration that parenteral is used.Thereby in another embodiment, using of the antisense compounds of target PCSK9 nucleic acid is that intravenously is used or subcutaneous administration.Use the antisense compounds of the target PCSK9 nucleic acid that can comprise a plurality of dosage or multi-agent.

In certain embodiments, the pharmaceutical composition that comprises the antisense compounds of target PCSK9 is used for using in therapy.In certain embodiments, described therapy is LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp (a), S-TG, liver tri-glyceride, Ox-LDL-C, little LDL particle, little VLDL, phosphatide or the oxidized phospholipids that reduces in the individuality.In certain embodiments, described therapy is hypercholesterolemia, mixed type dyslipidemia, atherosclerosis, incidence of atherosclerosis risk, coronary heart disease, acute coronary syndrome, coronary disease medical history, the treatment of tuinga worry, one or more coronary heart disease risk factors, type ii diabetes, the type ii diabetes with dyslipidemia, dyslipidemia, HTC, hyperlipidaemia, high fatty acid mass formed by blood stasis, fatty degeneration of liver, nonalcoholic fatty liver disease or non-alcoholic fatty liver disease early.In other embodiment, described therapy is to reduce the CHD risk.In certain aspects, described therapy is atherosclerotic prevention.In certain embodiments, described therapy is the prevention of coronary heart disease.

In certain embodiments, the pharmaceutical composition that comprises the antisense compounds of target PCSK9 is used for the medicine that preparation reduces individuality LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp (a), S-TG, liver tri-glyceride, Ox-LDL-C, little LDL particle, little VLDL, phosphatide or oxidized phospholipids.In specific embodiments, the pharmaceutical composition that comprises the antisense compounds of target PCSK9 is used to prepare the medicine that reduces coronary heart disease risk.In certain embodiments, the antisense compounds of target PCSK9 is used to prepare treatment hypercholesterolemia, mixed type dyslipidemia, atherosclerosis, incidence of atherosclerosis risk, coronary heart disease, coronary disease medical history, the medicine of tuinga worry, one or more coronary heart disease risk factors, type ii diabetes, the type ii diabetes with dyslipidemia, dyslipidemia, HTC, hyperlipidaemia, high fatty acid mass formed by blood stasis, fatty degeneration of liver, nonalcoholic fatty liver disease or non-alcoholic fatty liver disease early.

Some combination treatment

In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other medicaments are used altogether.In certain embodiments, described one or more other medicaments are designed for disease or the illness identical with described one or more medicine composite for curing of the present invention.In certain embodiments, described one or more other medicaments are designed for disease or the illness different with described one or more medicine composite for curing of the present invention.In certain embodiments, described one or more other medicaments are designed for the undesirable action of described one or more pharmaceutical compositions of the present invention of treatment.In certain embodiments, one or more pharmaceutical compositions of the present invention and another kind of medicament are used the undesirable action for the treatment of this another kind medicament altogether.In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other medicaments are used at one time.In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other medicaments are used at different time.In certain embodiments, one or more pharmaceutical compositions of the present invention are prepared in single preparaton with one or more other medicaments.In certain embodiments, one or more other medicaments of pharmaceutical composition of the present invention and one or more separate preparation.

In certain embodiments, can comprise lipid lowering agent or lxr agonist with the medicament that pharmaceutical composition of the present invention is used altogether.In some such embodiment, can include but not limited to atorvastatin (atorvastatin), Simvastatin (simvastatin), superstatin (rosuvastatin) and ezetimibe (ezetimibe) with the medicament that pharmaceutical composition of the present invention is used altogether.In some such embodiment, before using pharmaceutical composition of the present invention, use described lipid lowering agent.In some such embodiment, after using pharmaceutical composition of the present invention, use described lipid lowering agent.In some such embodiment, lipid lowering agent and pharmaceutical composition of the present invention are used at one time.In some such embodiment, the application dosage the when dosage of the lipid lowering agent of using is altogether used separately with this lipid lowering agent is identical.In some such embodiment, the application dosage that the dosage of the lipid lowering agent of using altogether is lower than this lipid lowering agent when using separately.In some such embodiment, the application dosage that the dosage of the lipid lowering agent of using altogether is higher than this lipid lowering agent when using separately.

In certain embodiments, the lipid lowering agent of using altogether is the HMG-CoA reductase inhibitor.In some such embodiment, described HMG-CoA reductase inhibitor is statins (statin).In some such embodiment, described statins is selected from, for example, and atorvastatin, Simvastatin, Pravastatin (pravastatin), fluvastatin (fluvastatin) and superstatin.

In certain embodiments, the lipid lowering agent of using altogether is a cholesterol absorption inhibitor.In some such embodiment, cholesterol absorption inhibitor is that the pool is for the rice shellfish.

In certain embodiments, the lipid lowering agent of using altogether is the HMG-CoA reductase inhibitor and the cholesterol absorption inhibitor of common preparation.In some such embodiment, the described lipid lowering agent of preparation altogether is that the pool is for rice shellfish/Simvastatin.

In certain embodiments, the lipid lowering agent of using altogether is microsome tri-glyceride transfer protein inhibitors (a MTP inhibitor).

In certain embodiments, the lipid lowering agent of using altogether is the oligonucleotide of target ApoB.

In certain embodiments, a kind of medicament of using altogether is bile acid chelating agent (bile acidsequestrant).In some such embodiment, described bile acid chelating agent is selected from Colestyramine (cholestyramine), colestipol (colestipol) and colesevelam (colesevelam).

In certain embodiments, the medicament of using altogether is nicotinic acid (nicotinic acid).In some such embodiment, described nicotinic acid is selected from instant-free nicotinic acid (immediate release nicotinic acid), prolongs release nicotinic acid (extended release nicotinic acid) and continues to discharge nicotinic acid (sustainedrelease nicotinic acid).

In certain embodiments, the medicament of using altogether is Carboxymethylcellulose (fibric acid).In some such embodiment, Carboxymethylcellulose is selected from gemfibrozil (gemfibrozil), fenofibrate (fenofibrate), clofibrate (clofibrate), bezafibrate (bezafibrate) and Win-35833 (ciprofibrate).

Other example of the medicament that can use altogether with pharmaceutical composition of the present invention includes but not limited to: reflunomide (corticosteroids) includes but not limited to prednisone (prednisone); Lxr agonist; Immunoglobulin (Ig) includes but not limited to intravenously immunoglobulin (Ig) (IVIg); Anodyne (analgesics) (for example acetaminophen (acetaminophen)); Anti-inflammatory agent (anti-inflammatory agents) includes but not limited to on-steroidal AID (for example Ibuprofen BP/EP (ibuprofen), COX-1 inhibitor and cox 2 inhibitor); Salicylate or ester (salicylates); Resistance element (antibiotics); Antiviral drug (antivirals); Anti-mycotic agent (antifungal agents); Antidiabetic drug (for example biguanides (biguanides), alpha-glucosidase inhibitors, Regular Insulin, sulfonylurea (sulfonylureas) and thiazolidinedione (thiazolidenediones)); Suprarenal gland energy modifier (adrenergic modifiers); Diuretic(s) (diuretics); Hormone (hormones) (for example anabolic steroid (anabolic steroids), male sex hormone (androgen), oestrogenic hormon (estrogen), thyrocalcitonin (calcitonin), progestin (progestin), somatostatin (somatostatin) and Triiodothyronine); Immunomodulator (immunomodulators); Muscular flaccidity agent (musclerelaxants); Antihistaminic (antihistamines); Osteoporosis drug (osteoporosis agents) (for example diphosphonate (biphosphonates), thyrocalcitonin and oestrogenic hormon); Prostaglandin(PG) (prostaglandins); Antitumour drug (antineoplastic agents); Psychotropic drug (psychotherapeutic agents); Tranquilizer (sedatives); Poison Oak Tree or black poison wood product (poison oak or poison sumac products); Antibody; And vaccine.

In certain embodiments, pharmaceutical composition of the present invention can be united with the lipopenicillinase therapy and used.In some such embodiment, a kind of lipopenicillinase therapy is that curative mode of life changes.In some such embodiment, a kind of lipopenicillinase therapy is that LDL removes (LDL apheresis).

Antisense compounds

Oligomeric compounds includes but not limited to: oligonucleotide, oligonucleoside, oligonucleotide analogs, oligonucleotide mimetic, antisense compounds, antisense oligonucleotide and siRNA.Oligomeric compounds can be for target nucleic acid " antisense ", and the meaning is that it can be hybridized by hydrogen bonding and target nucleic acid.

In certain embodiments, antisense compounds has such nuclear base sequence: when from 5 ' to 3 ' direction was write, this sequence comprised the reverse complementary sequence of the target area section of its target in the target nucleic acid.In some such embodiment, antisense oligonucleotide has such nuclear base sequence: when from 5 ' to 3 ' direction was write, this sequence comprised the reverse complementary sequence of the target area section of its target in the target nucleic acid.

In certain embodiments, the length of the antisense compounds of target PCSK9 nucleic acid is 8-80,12-50 is individual, 12-30 is individual or 15-30 subunit.In other words, antisense compounds is 8-80,12-50 is individual, 12-30 is individual or 15-30 subunit that is connected.In some such embodiment, the length of described antisense compounds is 12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 subunits.

In certain embodiments, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 12-30 Nucleotide.In some such embodiment, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 Nucleotide.

In certain embodiments, the length of the antisense compounds of target PCSK9 nucleic acid is 15-30 subunit.In other words, antisense compounds is a 15-30 subunit that is connected.In some such embodiment, the length of described antisense compounds is 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 subunits.

In certain embodiments, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 15-30 Nucleotide.In some such embodiment, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 Nucleotide.

In certain embodiments, the length of the antisense compounds of target PCSK9 nucleic acid is 18-24 subunit.In other words, antisense compounds is a 18-24 subunit that is connected.In one embodiment, the length of described antisense compounds is 18,19,20,21,22,23 or 24 subunits.

In certain embodiments, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 18-24 Nucleotide.In some such embodiment, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 18,19,20,21,22,23 or 24 Nucleotide.

In certain embodiments, the length of the antisense compounds of target PCSK9 nucleic acid is 19-22 subunit.In other words, antisense compounds is a 19-22 subunit that is connected.This represents length is the antisense compounds of 19,20,21 or 22 subunits.

In certain embodiments, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 19-22 Nucleotide.In some such embodiment, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 19,20,21 or 22 Nucleotide.

In certain embodiments, the length of the antisense compounds of target PCSK9 nucleic acid is 20 subunits.In some such embodiment, the length of antisense compounds is 20 subunits that are connected.

In certain embodiments, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 20 Nucleotide.In some such embodiment, the length of the antisense oligonucleotide of target PCSK9 nucleic acid is 20 Nucleotide that are connected.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains a kind of core sequence of 8 Nucleotide at least jointly.In certain embodiments, these targeting compounds of sharing a kind of 8 Nucleotide core sequences at least zone of identifying herein.

In certain embodiments, but the following Nucleotide zone of the antisense compounds target SEQ ID NO:1 of target PCSK9 nucleic acid:

294-317,406-440,406-526,410-436,410-499,446-526,545-581,591-619,591-704,591-743,595-622,600-626,600-639,600-670,601-628,602-628,603-630,611-636,620-647,638-665,648-674,657-684,705-743,782-810,821-859,835-859,835-917,835-942,860-887,860-899,860-909,860-917,869-895,878-905,888-909,923-952,960-1034,960-1173,960-986,967-991,970-1023,970-1064,970-1117,970-996,977-1004,985-1011,989-1016,992-1019,997-1024,997-1024,998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076-1096,1088-1115,1098-1123,1200-1251,1210-1237,1219-1245,1228-1251,1273-1444,1295-1316,1318-1345,1328-1354,1337-1361,1344-1371,1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526-1624,1532-1558,1541-1568,1552-1579,1560-1587,1561-1589,1564-1591,1565-1592,1566-1592,1567-1592,1570-1597,1571-1599,1605-1706,1628-1706,1640-1666,1672-1698,1681-1706,1735-1761,1735-1765,1740-1765,1849-1876,1849-1879,1850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854-1879,1905-1955,1915-1942,1916-1943,1917-1944,1918-1945,1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040-2126,2100-2126,2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227-3456,3472-3496 or 3543-3569.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, these share the following Nucleotide zone of the targeting compounds SEQ ID:1 of one 8 Nucleotide core sequence at least:

294-317,406-440,406-526,410-436,410-499,446-526,545-581,591-619,591-704,591-743,595-622,600-626,600-639,600-670,601-628,602-628,603-630,611-636,620-647,638-665,648-674,657-684,705-743,782-810,821-859,835-859,835-917,835-942,860-887,860-899,860-909,860-917,869-895,878-905,888-909,923-952,960-1034,960-1173,960-986,967-991,970-1023,970-1064,970-1117,970-996,977-1004,985-1011,989-1016,992-1019,997-1024,997-1024,998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076-1096,1088-1115,1098-1123,1200-1251,1210-1237,1219-1245,1228-1251,1273-1444,1295-1316,1318-1345,1328-1354,1337-1361,1344-1371,1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526-1624,1532-1558,1541-1568,1552-1579,1560-1587,1561-1589,1564-1591,1565-1592,1566-1592,1567-1592,1570-1597,1571-1599,1605-1706,1628-1706,1640-1666,1672-1698,1681-1706,1735-1761,1735-1765,1740-1765,1849-1876,1849-1879,1850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854-1879,1905-1955,1915-1942,1916-1943,1917-1944,1918-1945,1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040-2126,2100-2126,2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227-3456,3472-3496 or 3543-3569.

In certain embodiments, but the following Nucleotide zone of the antisense compounds target SEQ ID NO:2 of target PCSK9 nucleic acid:

2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667-5686,6444-6463,6482-6518,6492-6518,6528-6555,6528-623,6534-6561,6535-6562,6536-6563,6537-6563,6538-6565,6539-6565,6540-6567,6541-6567,6542-6569,6546-6573,6557-6584,6575-6602,6585-6611,6594-6621,6596-6623,6652-6671,7099-7118,7556-7584,8836-8855,8948-8967,9099-9118,9099-9168,9130-9168,9207-9233,9207-9235,9209-9235,10252-10271,10633-10652,11308-11491,12715-12734,12928-12947,13681-13700,13746-13779,13816-13847,13903-13945,13977-14141,14179-14198,14267-14286,14397-14423,14441-14460,14494-14513,14494-14543,14524-14543,14601-14650,14670-14700,14675-14700,14801-14828,14877-14912,14877-14915,14877-14973,14916-14943,14916-14973,14925-14951,14934-14963,14946-14973,14979-14998,15254-15280,15254-15328,15264-15290,15279-15305,15291-15318,15292-15319,15293-15320,15294-15321,15294-15321,15295-15322,15296-15323,15297-15323,15298-15323,15299-15323,15300-15323,15301-15328,15330-15355,15330-15490,15339-15366,15358-15490,16134-16153,16668-16687,17267-17286,18377-18427,18561-18580,18591-18618,18591-18646,18591-18668,18695-18746,18705-18730,18709-18736,18719-18746,19203-20080,19931-19952,19954-19981,19964-19990,19973-19999,19982-20009,19992-20016,20016-20042,20025-20052,20036-20062,20045-20070,20100-20119,20188-20207,20624-20650,20624-20759,20629-20804,20633-20660,20635-20781,20643-20662,20657-20676,20670-20697,20680-20706,20683-20781,20689-20715,20698-20725,20709-20736,20717-20744,20718-20745,20719-20746,20720-20747,20721-20748,20722-20749,20727-20752,20735-20759,20762-21014,20785-21014,21082-21107,21082-21152,21091-21114,21118-21144,21127-21152,21181-21209,21181-21211,21183-21211,21481-21500,21589-21608,21692-21719,22000-22227,22096-22115,22096-22223,22096-22311,22133-22160,22133-22163,22134-22161,22135-22162,22136-22163,22137-22163,22138-22163,22189-22239,22199-22226,22199-22227,22200-22227,22201-22228,22202-22229,22203-22230,22204-22231,22205-22232,22206-22233,22207-22234,22208-22235,22209-22236,22210-22236,22210-22239,22211-22236,22212-22239,22292-22311,23985-24054,24035-24134,24095-24121,24858-24877,24907-24926,25413-25432,25994-26013,26112-26139,26112-26161,26112-27303,26113-26140,26114-26141,26115-26141,26116-26141,26117-26141,26117-26475,26118-26141,26120-26141,26132-26151,26142-26161,26217-26241,26311-26335,26389-26432,26456-26576,26635-26662,26707-26734,26707-26736,26790-26820,27034-27263,27279-27303 or 27350-27376.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, these share the following Nucleotide zone of the targeting compounds SEQ ID:2 of one 8 Nucleotide core sequence at least:

2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667-5686,6444-6463,6482-6518,6492-6518,6528-6555,6528-6623,6534-6561,6535-6562,6536-6563,6537-6563,6538-6565,6539-6565,6540-6567,6541-6567,6542-6569,6546-6573,6557-6584,6575-6602,6585-6611,6594-6621,6596-6623,6652-6671,7099-7118,7556-7584,8836-8855,8948-8967,9099-9118,9099-9168,9130-9168,9207-9233,9207-9235,9209-9235,10252-10271,10633-10652,11308-11491,12715-12734,12928-12947,13681-13700,13746-13779,13816-13847,13903-13945,13977-14141,14179-14198,14267-14286,14397-14423,14441-14460,14494-14513,14494-14543,14524-14543,14601-14650,14670-14700,14675-14700,14801-14828,14877-14912,14877-14915,14877-14973,14916-14943,14916-14973,14925-14951,14934-14963,14946-14973,14979-14998,15254-15280,15254-15328,15264-15290,15279-15305,15291-15318,15292-15319,15293-15320,15294-15321,15294-15321,15295-15322,15296-15323,15297-15323,15298-15323,15299-15323,15300-15323,15301-15328,15330-15355,15330-15490,15339-15366,15358-15490,16134-16153,16668-16687,17267-17286,18377-18427,18561-18580,18591-18618,18591-18646,18591-18668,18695-18746,18705-18730,18709-18736,18719-18746,19203-20080,19931-19952,19954-19981,19964-19990,19973-19999,19982-20009,19992-20016,20016-20042,20025-20052,20036-20062,20045-20070,20100-20119,20188-20207,20624-20650,20624-20759,20629-20804,20633-20660,20635-20781,20643-20662,20657-20676,20670-20697,20680-20706,20683-20781,20689-20715,20698-20725,20709-20736,20717-20744,20718-20745,20719-20746,20720-20747,20721-20748,20722-20749,20727-20752,20735-20759,20762-21014,20785-21014,21082-21107,21082-21152,21091-21114,21118-21144,21127-21152,21181-21209,21181-21211,21183-21211,21481-21500,21589-21608,21692-21719,22000-22227,22096-22115,22096-22223,22096-22311,22133-22160,22133-22163,22134-22161,22135-22162,22136-22163,22137-22163,22138-22163,22189-22239,22199-22226,22199-22227,22200-22227,22201-22228,22202-22229,22203-22230,22204-22231,22205-22232,22206-22233,22207-22234,22208-22235,22209-22236,22210-22236,22210-22239,22211-22236,22212-22239,22292-22311,23985-24054,24035-24134,24095-24121,24858-24877,24907-24926,25413-25432,25994-26013,26112-26139,26112-26161,26112-27303,26113-26140,26114-26141,26115-26141,26116-26141,26117-26141,26117-26475,26118-26141,26120-26141,26132-26151,26142-26161,26217-26241,26311-26335,26389-26432,26456-26576,26635-26662,26707-26734,26707-26736,26790-26820,27034-27263,27279-27303 or 27350-27376.

In certain embodiments, but the following Nucleotide zone of the antisense compounds target SEQ ID NO:3 of target PCSK9 nucleic acid:

220-253,290-321,377-419,451-615,653-672,741-760,871-897,915-934,968-1017,1075-1124,1075-1174,1144-1174,1275-1302,1315-1341,1351-1389,1351-1447,1365-1439,1390-1417,1390-1429,1390-1439,1399-1425,1408-1435,1420-1447,1453-1482,1490-1516,1490-1564,1500-1526,1515-1541,1527-1553,1527-1554,1528-1554,1529-1555,1529-1556,1530-1556,1530-1557,1531-1557,1532-1558,1533-1559,1534-1559,1535-1559,1536-1559,1537-1564,1566-1602,1566-1681,1606-1626,1618-1645,1626-1653,1684-1703,1730-1781,1740-1767,1749-1775,1758-1781,1820-1847,1820-1877,1822-2198,1830-1856,1839-1865,1840-1867,1898-1924,1898-2035,1903-2127,1907-1934,1911-1938,1946-1971,1954-1980,1959-2035,1959-2057,1963-1988,1967-2035,1972-1999,1982-2008,1991-2018,1993-2019,1995-2022,1996-2023,1997-2024,1998-2025,1999-2025,2000-2025,2009-2035,2038-2139,2061-2139,2073-2099,2078-2104,2105-2131,2112-2139,2168-2198,2170-2177,2245-2284,2295-2394,2355-2381,2355-2394,2405-2461,2560-2587,2560-2609,2561-2588,2562-2589,2563-2589,2564-2589,2565-2589,2566-2589,2567-2589,2568-2589,2665-2689,2759-2783,2837-2880,2904-2923,3005-3024,3005-3174,3083-3110,3155-3184,3238-3268,3482-3711,3727-3751 or 3798-3824.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, these share the following Nucleotide zone of the targeting compounds SEQ ID:3 of one 8 Nucleotide core sequence at least:

220-253,290-321,377-419,451-615,653-672,741-760,871-897,915-934,968-1017,1075-1124,1075-1174,1144-1174,1275-1302,1315-1341,1351-1389,1351-1447,1365-1439,1390-1417,1390-1429,1390-1439,1399-1425,1408-1435,1420-1447,1453-1482,1490-1516,1490-1564,1500-1526,1515-1541,1527-1553,1527-1554,1528-1554,1529-1555,1529-1556,1530-1556,1530-1557,1531-1557,1532-1558,1533-1559,1534-1559,1535-1559,1536-1559,1537-1564,1566-1602,1566-1681,1606-1626,1618-1645,1626-1653,1684-1703,1730-1781,1740-1767,1749-1775,1758-1781,1820-1847,1820-1877,1822-2198,1830-1856,1839-1865,1840-1867,1898-1924,1898-2035,1903-2127,1907-1934,1911-1938,1946-1971,1954-1980,1959-2035,1959-2057,1963-1988,1967-2035,1972-1999,1982-2008,1991-2018,1993-2019,1995-2022,1996-2023,1997-2024,1998-2025,1999-2025,2000-2025,2009-2035,2038-2139,2061-2139,2073-2099,2078-2104,2105-2131,2112-2139,2168-2198,2170-2177,2245-2284,2295-2394,2355-2381,2355-2394,2405-2461,2560-2587,2560-2609,2561-2588,2562-2589,2563-2589,2564-2589,2565-2589,2566-2589,2567-2589,2568-2589,2665-2689,2759-2783,2837-2880,2904-2923,3005-3024,3005-3174,3083-3110,3155-3184,3238-3268,3482-3711,3727-3751 or 3798-3824.

In certain embodiments, but the following Nucleotide zone of the antisense compounds target SEQ ID NO:1 of target PCSK9 nucleic acid:

320-405,441-445,527-544,582-590,744-781,811-820,918-922,953-959,1034-1036,1152-1153,1174-1199,1251-1272,1445-1464,1603-1604,1625-1627,1707-1734,1766-1811,1832-1848,1880-1904,1956-1961,1982-1939,2030-2039,2060-2099,2140-2149,2170-2186,2207-2304,2355-2409,2435-2503,2529-2581,2626-2648,2669-2749,2770-2827,2856-2876,2891-2899,2930-2982,3014-3226,3253-3436,3457-3471 or 3497-3542.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, these share the following Nucleotide zone of the targeting compounds SEQ ID:1 of one 8 Nucleotide core sequence at least:

320-405,441-445,527-544,582-590,744-781,811-820,918-922,953-959,1034-1036,1152-1153,1174-1199,1251-1272,1445-1464,1603-1604,1625-1627,1707-1734,1766-1811,1832-1848,1880-1904,1956-1961,1982-1939,2030-2039,2060-2099,2140-2149,2170-2186,2207-2304,2355-2409,2435-2503,2529-2581,2626-2648,2669-2749,2770-2827,2856-2876,2891-2899,2930-2982,3014-3226,3253-3436,3457-3471 or 3497-3542.

In certain embodiments, shorten the antisense compounds of the target PCSK9 nucleic acid of (shortened) or brachymemma (truncated) and delete single subunit (5 ' brachymemma), perhaps delete single subunit from 3 ' the terminal single subunit of deletion (3 ' brachymemma) from 5 ' end.The antisense compounds of the target PCSK9 nucleic acid of shortening or brachymemma can perhaps be deleted two subunits from 3 ' end of this antisense compounds from two subunits of 5 ' terminal deletion of this antisense compounds.Perhaps, the nucleosides of deletion may be interspersed within the whole antisense compounds, for example, and in the antisense compounds of a 5 ' nucleosides of terminal deletion and a nucleosides of 3 ' terminal deletion.

When the subunit of single interpolation was present in the antisense compounds of prolongation (lengthened), the subunit of this interpolation can be positioned at 5 ' or 3 ' end of this antisense compounds.When having the subunit of two or more interpolations, the subunit of interpolation can be adjacent to each other, and for example, adds in the antisense compounds of two subunits (3 ' adds) in two subunits of 5 ' terminal interpolation (5 ' adds) or 3 ' end.Perhaps, the subunit of interpolation may be interspersed within the whole antisense compounds, for example, and in the antisense compounds of a 5 ' subunit of terminal interpolation and a subunit of 3 ' terminal interpolation.

Can increase or reduce the length of antisense compounds (such as antisense oligonucleotide) and/or introduce base mismatch and eliminate activity not.For example, at Woolf etc., Proc.Natl.Acad.Sci.USA 89:7305-7309, in 1992, the antisense oligonucleotide of having tested a series of long 13-25 nuclear bases is induced the ability of target RNA cutting in the ovocyte injection model.There is the antisense oligonucleotide of 8 or 11 base mismatch can instruct the specificity of said target mrna to cut near long 25 nuclear bases and its end, although its degree is lower than the antisense oligonucleotide that does not contain mispairing.Similarly, use the antisense oligonucleotide (comprise those have 1 or 3 mispairing) of 13 nuclear bases to realize the cutting of target thing specificity.

Gautschi etc., J.Natl.Cancer Inst.93:463-471, March 2001 have shown with bcl-2mRNA to have oligonucleotide that 100% complementary and relative bcl-xL mRNA has 3 mispairing external and reduce the two the ability of expression of bcl-2 and bcl-xL in vivo.In addition, this oligonucleotide shows strong anti-tumor activity in vivo.

Maher and Dolnick, Nuc.Acid.Res.16:3341-3358,1988 have tested a series of series connection 14 nuclear base antisense oligonucleotides and the 28 and 42 nuclear base antisense oligonucleotides that are made of the sequence of two or three such series connection antisense oligonucleotides respectively blocks the ability that people DHFR translates in rabbit reticulocyte determination method.The antisense oligonucleotide of three kind of 14 nuclear base all can suppress translation individually, although its inhibition level is lower than the antisense oligonucleotide of described 28 or 42 nuclear bases.

PCT/US2007/068404 has put down in writing the high-affinity Nucleotide that mixes through chemically modified in the long short antisense compounds of about 8-16 nuclear base, and to have put down in writing such compound be useful aspect the target RNA in the therapeutic index reduction animal of the effectiveness that raises and improvement.

In certain embodiments, the antisense compounds of target PCSK9 nucleic acid is short antisense compounds.In certain embodiments, so short antisense compounds is the oligonucleotide compound.In certain embodiments, short antisense compounds like this is for individual, preferred 9-15 of about 8-16, more preferably 9-14 is individual, more preferably 10-14 Nucleotide is long, and comprise relief area, each side flank of this breach is the wing (wing), and wherein each wing is made up of 1-3 Nucleotide independently.Preferred motif includes but not limited to be selected from down the wing-deoxidation breach-wing motif: 3-10-3,2-10-3,2-10-2,1-10-1,2-8-2,1-8-1,3-6-3 or the 1-6-1 of group.

The antisense compounds of target PCSK9 nucleic acid is external synthetic, does not comprise the antisense composition of biogenetic derivation or is designed for synthetic genophore construct in the body that instructs antisense molecule.

In certain embodiments, the zone that does not contain single nucleotide polymorphism (SNP) in the antisense compounds target PCSK9 nucleic acid.In certain embodiments, the zone of containing single nucleotide polymorphism (SNP) in the antisense compounds target PCSK9 nucleic acid.Single nucleotide polymorphism is meant because the change of single Nucleotide or the polymorphism that causes owing to there are two or more optional sequences (for example, can be the different equipotential forms of a gene).Polymorphism can comprise one or more bases and change, and for example insert, repeat, or deletion.In certain embodiments, the antisense oligonucleotide of target PCSK9 nucleic acid overlaps at following column position and SNP: 428,432,449,996,1011,1044,1317,1565,1617,1618,1671,1711,1722,1836,1911.In certain embodiments, the compound that contains the zone of one or more SNP in the target PCSK9 nucleic acid provided herein will comprise suitable base to be substituted, insert, repeats or deletion, makes this compound complementary fully with the PCSK9 nucleotide sequence through changing.

The antisense compounds motif

In certain embodiments, the antisense compounds of target PCSK9 nucleic acid has the chemically modified subunit that is arranged in pattern (pattern) or motif (motif), with give this antisense compounds with suppress active such as enhanced, increase to the binding affinity of target nucleic acid or at the character such as resistance of nucleic acid in vivo enzyme liberating.

Chimeric antisense compounds typically contains at least one such zone, its modified cellular uptake with the resistance at nuclease degradation of giving increase, increase, increase to the binding affinity of target nucleic acid and/or the inhibition activity that increases.The substrate of cell endonuclease ribozyme enzyme H can be served as in another zone of chimeric antisense compounds, the RNA chain of this kind of enzyme cutting RNA:DNA duplex.

Antisense compounds with breach polymers (gapmer) motif is considered as chimeric antisense compounds.In the breach polymers, interior location (internal position) is positioned between the external region (external regions), described interior location has a plurality of Nucleotide of supporting RNA enzyme H cutting, and described external region has a plurality of Nucleotide at the nucleosides that chemically differs from interior region.In the situation of antisense oligonucleotide, serve as the substrate of endonuclease cutting usually by the breach section, and the pterion section comprises the nucleosides of modification with breach polymers motif.Each zone of breach polymers is distinguished mutually by the sugared type of module that constitutes each unique zone.The sugared type of module that is used for distinguishing each zone of breach polymers can comprise that in some embodiment (such 2 '-nucleosides of modifying can comprise 2 '-MOE and 2 '-O-CH for the nucleosides of β-D-ribonucleoside, β-D-dezyribonucleoside, 2 '-modification ₃Or the like) and the sugar-modified nucleosides of dicyclo (the sugar-modified nucleosides of such dicyclo can comprise that those have the nucleosides of 4 '-(CH2) n-O-2 ' bridge, wherein n=1 or n=2).Generally speaking, the sugared module that comprises of each unique zone is consistent.The wing-breach-wing motif often is described to " X-Y-Z ", and wherein " X " represents the length in 5 ' pterion, and " Y " represents the length of relief area, and " Z " represents the length in 3 ' pterion.

In some embodiments, the antisense compounds of target PCSK9 nucleic acid has the motif that breach is widened (widened).In other embodiments, the antisense oligonucleotide of target PCSK9 nucleic acid has the motif that breach is widened.

Breach described herein is widened antisense oligonucleotide and can be had and be selected from the following various wing-breach-wing motif:

1-16-1，2-15-1，1-15-2，1-14-3，3-14-1，2-14-2，1-13-4，4-13-1，2-13-3，3-13-2，1-12-5，5-12-1，2-12-4，4-12-2，3-12-3，1-11-6，6-11-1，2-11-5，5-11-2，3-11-4，4-11-3，1-17-1，2-16-1，1-16-2，1-15-3，3-15-1，2-15-2，1-14-4，4-14-1，2-14-3，3-14-2，1-13-5，5-13-1，2-13-4，4-13-2，3-13-3，1-12-6，6-12-1，2-12-5，5-12-2，3-12-4，4-12-3，1-11-7，7-11-1，2-11-6，6-11-2，3-11-5，5-11-3，4-11-4，1-18-1，1-17-2，2-17-1，1-16-3，1-16-3，2-16-2，1-15-4，4-15-1，2-15-3，3-15-2，1-14-5，5-14-1，2-14-4，4-14-2，3-14-3，1-13-6，6-13-1，2-13-5，5-13-2，3-13-4，4-13-3，1-12-7，7-12-1，2-12-6，6-12-2，3-12-5，5-12-3，4-12-4，1-11-8，8-11-1，2-11-7，7-11-2，3-11-6，6-11-3，4-11-5，5-11-4，1-18-1，1-17-2，2-17-1，1-16-3，3-16-1，2-16-2，1-15-4，4-15-1，2-15-3，3-15-2，1-14-5，2-14-4，4-14-2，3-14-3，1-13-6，6-13-1，2-13-5，5-13-2，3-13-4，4-13-3，1-12-7，7-12-1，2-12-6，6-12-2，3-12-5，5-12-3，4-12-4，1-11-8，8-11-1，2-11-7，7-11-2，3-11-6，6-11-3，4-11-5，5-11-4，1-19-1，1-18-2，2-18-1，1-17-3，3-17-1，2-17-2，1-16-4，4-16-1，2-16-3，3-16-2，1-15-5，2-15-4，4-15-2，3-15-3，1-14-6，6-14-1，2-14-5，5-14-2，3-14-4，4-14-3，1-13-7，7-13-1，2-13-6，6-13-2，3-13-5，5-13-3，4-13-4，1-12-8，8-12-1，2-12-7，7-12-2，3-12-6，6-

12-3,4-12-5,5-12-4,2-11-8,8-11-2,3-11-7,7-11-3,4-11-6,6-11-4,5-11-5,1-20-1,1-19-2,2-19-1,1-18-3,3-18-1,2-18-2,1-17-4,4-17-1,2-17-3,3-17-2,1-16-5,2-16-4,4-16-2,3-16-3,1-15-6,6-15-1,2-15-5,5-15-2,3-15-4,4-15-3,1-14-7,7-14-1,2-14-6,6-14-2,3-14-5,5-14-3,4-14-4,1-13-8,8-13-1,2-13-7,7-13-2,3-13-6,6-13-3,4-13-5,5-13-4,2-12-8,8-12-2,3-12-7,7-12-3,4-12-6,6-12-4,5-12-5,3-11-8,8-11-3,4-11-7,7-11-4,5-11-6,6-11-5,1-21-1,1-20-2,2-20-1,1-20-3,3-19-1,2-19-2,1-18-4,4-18-1,2-18-3,3-18-2,1-17-5,2-17-4,4-17-2,3-17-3,1-16-6,6-16-1,2-16-5,5-16-2,3-16-4,4-16-3,1-15-7,7-15-1,2-15-6,6-15-2,3-15-5,5-15-3,4-15-4,1-14-8,8-14-1,2-14-7,7-14-2,3-14-6,6-14-3,4-14-5,5-14-4,2-13-8,8-13-2,3-13-7,7-13-3,4-13-6,6-13-4,5-13-5,1-12-10,10-12-1,2-12-9,9-12-2,3-12-8,8-12-3,4-12-7,7-12-4,5-12-6,6-12-5,4-11-8,8-11-4,5-11-7,7-11-5,6-11-6,1-22-1,1-21-2,2-21-1,1-21-3,3-20-1,2-20-2,1-19-4,4-19-1,2-19-3,3-19-2,1-18-5,2-18-4,4-18-2,3-18-3,1-17-6,6-17-1,2-17-5,5-17-2,3-17-4,4-17-3,1-16-7,7-16-1,2-16-6,6-16-2,3-16-5,5-16-3,4-16-4,1-15-8,8-15-1,2-15-7,7-15-2,3-15-6,6-15-3,4-15-5,5-15-4,2-14-8,8-14-2,3-14-7,7-14-3,4-14-6,6-14-4,5-14-5,3-13-8,8-13-3,4-13-7,7-13-4,5-13-6,6-13-5,4-12-8,8-12-4,5-12-7,7-12-5,6-12-6,5-11-8,8-11-5,6-11-7 or 7-11-6.

In some preferred embodiment, the motif that breach is widened includes but not limited to 2-13-5,3-14-3,3-14-4 breach polymers motif.

In one embodiment, the antisense oligonucleotide of the target PCSK9 nucleic acid that breach is widened has the breach section that contains 14 2 '-deoxynucleotides, and this relief area section is positioned between the pterion section of the nucleosides that contains 3 chemically modifieds.In one embodiment, described chemically modified comprise 2 '-sugar-modified.In another embodiment, described chemically modified comprises that 2 '-MOE is sugar-modified.

In one embodiment, the antisense compounds of target PCSK9 nucleic acid has 5-10-5 breach polymers motif.

Target nucleic acid, target region and nucleotide sequence

The nucleotide sequence of coding PCSK9 includes but not limited to following: Accession number NM_174936.2 is early than being stored on June 1st, 2003

This paper takes in as SEQ IDNO:1;

The Nucleotide 25475000 to 25504000 of accession number NT_032977.8 is early than being stored on February 26th, 2006

This paper takes in as SEQ ID NO:2; With

Accession number AK124635.1 is early than being stored on September 8th, 2003

This paper takes in as SEQ ID NO:3.

Some part that it should be noted these nucleotide sequences is shared identical sequence.For example, a plurality of parts of SEQ IDNO:1 are identical with a plurality of parts of SEQ ID NO:2; A plurality of parts of SEQ ID NO:1 are identical with a plurality of parts of SEQ ID NO:3; And a plurality of parts of SEQ ID NO:2 are identical with a plurality of parts of SEQ ID NO:3.Thereby the antisense compounds of target SEQ ID NO:1 is target SEQ IDNO:2 and/or SEQ ID NO:3 also; The antisense compounds of target SEQ ID NO:2 is target SEQ IDNO:1 and/or SEQ ID NO:3 also; And the antisense compounds of target SEQ ID NO:3 also target SEQID NO:1 and/or SEQ ID NO:2.The example of such antisense compounds is shown in following table.

In certain embodiments, the antisense compounds target has

(it is early than being stored on June 1st, 2003 for the sequence of accession number NM_174936.2

And as SEQ ID NO:1 income this paper) PCSK9 nucleic acid.In some such embodiment, antisense oligonucleotide target SEQ ID NO:1.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:1 and SEQ ID NO:1 at least 90% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:1 and SEQ ID NO:1 at least 95% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:1 and SEQ ID NO:1100% complementation.In certain embodiments, the antisense oligonucleotide of target SEQ ID NO:1 comprises the nucleotide sequence that is selected from the listed nucleotide sequence of table 1.

Table 1: the nucleotide sequence of target NM_174936.2 (SEQ ID NO:1)

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				4	135	154	GCGCGGAATCCTGGCTGGGA
5	242	261	GAGGAGACCTAGAGGCCGTG
				159	294	313	GCCTGGAGCTGACGGTGCCC
160	298	317	GACCGCCTGGAGCTGACGGT
				6	300	319	AGGACCGCCTGGAGCTGACG
162	406	425	AAGGCTAGCACCAGCTCCTC
				163	407	426	CAAGGCTAGCACCAGCTCCT
164	408	427	GCAAGGCTAGCACCAGCTCC
				165	409	428	CGCAAGGCTAGCACCAGCTC
7	410	429	ACGCAAGGCTAGCACCAGCT
				166	411	430	AACGCAAGGCTAGCACCAGC
167	412	431	GAACGCAAGGCTAGCACCAG
				168	413	432	GGAACGCAAGGCTAGCACCA
169	414	433	CGGAACGCAAGGCTAGCACC
				8	417	436	CCTCGGAACGCAAGGCTAGC
170	421	440	TCCTCCTCGGAACGCAAGGC
				171	446	465	GTGCTCGGGTGCTTCGGCCA
172	466	485	TGGAAGGTGGCTGTGGTTCC
				9	480	499	CCTTGGCGCAGCGGTGGAAG
173	482	501	ATCCTTGGCGCAGCGGTGGA
				174	484	503	GGATCCTTGGCGCAGCGGTG
175	488	507	CCACGGATCCTTGGCGCAGC
				176	507	526	CGTAGGTGCCAGGCAACCTC
177	545	564	TGACTGCGAGAGGTGGGTCT
				178	555	574	CAGTGCGCTCTGACTGCGAG
179	557	576	GGCAGTGCGCTCTGACTGCG
				180	559	578	CGGGCAGTGCGCTCTGACTG
10	561	580	GGCGGGCAGTGCGCTCTGAC
				181	562	581	CGGCGGGCAGTGCGCTCTGA
182	591	610	ATCCCCGGCGGGCAGCCTGG
				183	595	614	AGGTATCCCCGGCGGGCAGC
184	597	616	TGAGGTATCCCCGGCGGGCA
				185	598	617	GTGAGGTATCCCCGGCGGGC
186	599	618	GGTGAGGTATCCCCGGCGGG
				11	600	619	TGGTGAGGTATCCCCGGCGG
187	601	620	TTGGTGAGGTATCCCCGGCG
				188	602	621	CTTGGTGAGGTATCCCCGGC
189	603	622	TCTTGGTGAGGTATCCCCGG
				190	604	623	ATCTTGGTGAGGTATCCCCG
191	605	624	GATCTTGGTGAGGTATCCCC
				12	606	625	GGATCTTGGTGAGGTATCCC
192	607	626	AGGATCTTGGTGAGGTATCC
				193	609	628	GCAGGATCTTGGTGAGGTAT

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				194	611	630	ATGCAGGATCTTGGTGAGGT
195	613	632	ACATGCAGGATCTTGGTGAG
				13	615	634	AGACATGCAGGATCTTGGTG
196	617	636	GAAGACATGCAGGATCTTGG
				14	620	639	ATGGAAGACATGCAGGATCT
197	628	647	AGAAGGCCATGGAAGACATG
				198	638	657	GAAGCCAGGAAGAAGGCCAT
15	646	665	TTCACCAGGAAGCCAGGAAG
				199	648	667	TCTTCACCAGGAAGCCAGGA
16	651	670	TCATCTTCACCAGGAAGCCA
				200	653	672	ACTCATCTTCACCAGGAAGC
201	655	674	CCACTCATCTTCACCAGGAA
				202	657	676	CGCCACTCATCTTCACCAGG
203	659	678	GTCGCCACTCATCTTCACCA
				204	661	680	AGGTCGCCACTCATCTTCAC
205	663	682	GCAGGTCGCCACTCATCTTC
				206	665	684	CAGCAGGTCGCCACTCATCT
207	667	686	TCCAGCAGGTCGCCACTCAT
				208	685	704	GGCAACTTCAAGGCCAGCTC
17	705	724	CCTCGATGTAGTCGACATGG
				209	724	743	GCAAAGACAGAGGAGTCCTC
210	782	801	TTCATCCGCCCGGTACCGTG
				211	784	803	TATTCATCCGCCCGGTACCG
18	785	804	GTATTCATCCGCCCGGTACC
				212	787	806	TGGTATTCATCCGCCCGGTA
213	789	808	GCTGGTATTCATCCGCCCGG
				214	791	810	GGGCTGGTATTCATCCGCCC
215	821	840	ATACACCTCCACCAGGCTGC
				216	832	851	GTGTCTAGGAGATACACCTC
19	835	854	CTGGTGTCTAGGAGATACAC
				217	837	856	TGCTGGTGTCTAGGAGATAC
20	840	859	GTATGCTGGTGTCTAGGAGA
				21	860	879	GATTTCCCGGTGGTCACTCT
218	862	881	TCGATTTCCCGGTGGTCACT
				219	863	882	CTCGATTTCCCGGTGGTCAC
220	864	883	CCTCGATTTCCCGGTGGTCA
				221	865	884	CCCTCGATTTCCCGGTGGTC
22	866	885	GCCCTCGATTTCCCGGTGGT
				222	867	886	TGCCCTCGATTTCCCGGTGG
223	868	887	CTGCCCTCGATTTCCCGGTG
				224	869	888	CCTGCCCTCGATTTCCCGGT
225	870	889	CCCTGCCCTCGATTTCCCGG
				226	874	893	ATGACCCTGCCCTCGATTTC
227	876	895	CCATGACCCTGCCCTCGATT
				228	878	897	GACCATGACCCTGCCCTCGA
23	880	899	GTGACCATGACCCTGCCCTC
				229	882	901	CGGTGACCATGACCCTGCCC
230	884	903	GTCGGTGACCATGACCCTGC

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				231	886	905	AAGTCGGTGACCATGACCCT
232	888	907	CGAAGTCGGTGACCATGACC
				24	890	909	CTCGAAGTCGGTGACCATGA
233	898	917	GGCACATTCTCGAAGTCGGT
				25	923	942	GTGGAAGCGGGTCCCGTCCT
234	933	952	TGGCCTGTCTGTGGAAGCGG
				235	960	979	GGTGGGTGCCATGACTGTCA
236	963	982	CCAGGTGGGTGCCATGACTG
				237	967	986	CCTGCCAGGTGGGTGCCATG
26	970	989	ACCCCTGCCAGGTGGGTGCC
				238	972	991	CCACCCCTGCCAGGTGGGTG
27	975	994	TGACCACCCCTGCCAGGTGG
				239	977	996	GCTGACCACCCCTGCCAGGT
240	985	1004	TCCCGGCCGCTGACCACCCC
				241	989	1008	GGCATCCCGGCCGCTGACCA
242	992	1011	GCCGGCATCCCGGCCGCTGA
				243	997	1016	GCCACGCCGGCATCCCGGCC
244	998	1017	GGCCACGCCGGCATCCCGGC
				245	999	1018	TGGCCACGCCGGCATCCCGG
246	1000	1019	TTGGCCACGCCGGCATCCCG
				247	1001	1020	CTTGGCCACGCCGGCATCCC
248	1002	1021	CCTTGGCCACGCCGGCATCC
				249	1003	1022	CCCTTGGCCACGCCGGCATC
28	1004	1023	ACCCTTGGCCACGCCGGCAT
				447	1004	1023	ACCCTTGGTCACGCCGGCAT
250	1005	1024	CACCCTTGGCCACGCCGGCA
				251	1006	1025	GCACCCTTGGCCACGCCGGC
252	1007	1026	GGCACCCTTGGCCACGCCGG
				253	1008	1027	TGGCACCCTTGGCCACGCCG
254	1009	1028	CTGGCACCCTTGGCCACGCC
				255	1010	1029	GCTGGCACCCTTGGCCACGC
256	1015	1034	CGCATGCTGGCACCCTTGGC
				257	1036	1055	CAGTTGAGCACGCGCAGGCT
258	1038	1057	GGCAGTTGAGCACGCGCAGG
				29	1040	1059	TTGGCAGTTGAGCACGCGCA
259	1042	1061	CCTTGGCAGTTGAGCACGCG
				30	1045	1064	TTCCCTTGGCAGTTGAGCAC
260	1047	1066	CCTTCCCTTGGCAGTTGAGC
				261	1051	1070	GTGCCCTTCCCTTGGCAGTT
262	1053	1072	CCGTGCCCTTCCCTTGGCAG
				263	1064	1083	GGTGCCGCTAACCGTGCCCT
264	1076	1095	CAGGCCTATGAGGGTGCCGC
				31	1077	1096	CCAGGCCTATGAGGGTGCCG
458	1079	1092	GCCTATGAGGGTGC
				459	1084	1097	TCCAGGCCTATGAG
265	1088	1107	CCGAATAAACTCCAGGCCTA
				266	1096	1115	TGGCTTTTCCGAATAAACTC
32	1098	1117	GCTGGCTTTTCCGAATAAAC

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				267	1100	1119	CAGCTGGCTTTTCCGAATAA
268	1102	1121	ACCAGCTGGCTTTTCCGAAT
				269	1104	1123	GGACCAGCTGGCTTTTCCGA
270	1108	1127	GGCTGGACCAGCTGGCTTTT
				271	1119	1138	GTGGCCCCACAGGCTGGACC
272	1132	1151	AGCAGCACCACCAGTGGCCC
				273	1154	1173	GCTGTACCCACCCGCCAGGG
274	1200	1219	CGACCCCAGCCCTCGCCAGG
				33	1210	1229	GTGACCAGCACGACCCCAGC
275	1212	1231	CGGTGACCAGCACGACCCCA
				276	1214	1233	AGCGGTGACCAGCACGACCC
277	1216	1235	GCAGCGGTGACCAGCACGAC
				278	1218	1237	CGGCAGCGGTGACCAGCACG
279	1219	1238	CCGGCAGCGGTGACCAGCAC
				280	1222	1241	TTGCCGGCAGCGGTGACCAG
281	1224	1243	AGTTGCCGGCAGCGGTGACC
				282	1226	1245	GAAGTTGCCGGCAGCGGTGA
283	1228	1247	CGGAAGTTGCCGGCAGCGGT
				284	1230	1249	CCCGGAAGTTGCCGGCAGCG
285	1232	1251	GTCCCGGAAGTTGCCGGCAG
				286	1273	1292	ATGACCTCGGGAGCTGAGGC
287	1283	1302	CCCAACTGTGATGACCTCGG
				288	1295	1314	GGCATTGGTGGCCCCAACTG
149	1297	1316	TGGGCATTGGTGGCCCCAAC
				289	1305	1324	GCTGGTCTTGGGCATTGGTG
290	1318	1337	CCCAGGGTCACCGGCTGGTC
				291	1320	1339	TCCCCAGGGTCACCGGCTGG
292	1322	1341	AGTCCCCAGGGTCACCGGCT
				293	1324	1343	AAAGTCCCCAGGGTCACCGG
34	1326	1345	CCAAAGTCCCCAGGGTCACC
				294	1328	1347	CCCCAAAGTCCCCAGGGTCA
128	1330	1349	GTCCCCAAAGTCCCCAGGGT
				295	1333	1352	TTGGTCCCCAAAGTCCCCAG
35	1335	1354	AGTTGGTCCCCAAAGTCCCC
				296	1337	1356	AAAGTTGGTCCCCAAAGTCC
36	1340	1359	GCCAAAGTTGGTCCCCAAAG
				297	1342	1361	CGGCCAAAGTTGGTCCCCAA
298	1344	1363	AGCGGCCAAAGTTGGTCCCC
				299	1346	1365	ACAGCGGCCAAAGTTGGTCC
300	1348	1367	ACACAGCGGCCAAAGTTGGT
				301	1350	1369	CCACACAGCGGCCAAAGTTG
37	1352	1371	GTCCACACAGCGGCCAAAGT
				302	1354	1373	AGGTCCACACAGCGGCCAAA
303	1356	1375	AGAGGTCCACACAGCGGCCA
				304	1358	1377	AAAGAGGTCCACACAGCGGC
38	1361	1380	GGCAAAGAGGTCCACACAGC
				305	1380	1399	CAATGATGTCCTCCCCTGGG
306	1387	1406	GAGGCACCAATGATGTCCTC

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				39	1389	1408	TGGAGGCACCAATGATGTCC
307	1391	1410	GCTGGAGGCACCAATGATGT
				308	1393	1412	TCGCTGGAGGCACCAATGAT
309	1395	1414	AGTCGCTGGAGGCACCAATG
				310	1397	1416	GCAGTCGCTGGAGGCACCAA
40	1400	1419	GCTGCAGTCGCTGGAGGCAC
				311	1402	1421	GTGCTGCAGTCGCTGGAGGC
312	1404	1423	AGGTGCTGCAGTCGCTGGAG
				313	1406	1425	GCAGGTGCTGCAGTCGCTGG
314	1407	1426	AGCAGGTGCTGCAGTCGCTG
				315	1409	1428	AAAGCAGGTGCTGCAGTCGC
41	1411	1430	ACAAAGCAGGTGCTGCAGTC
				316	1413	1432	ACACAAAGCAGGTGCTGCAG
317	1415	1434	TGACACAAAGCAGGTGCTGC
				318	1425	1444	TCCCACTCTGTGACACAAAG
101	1465	1484	ATGGCTGCAATGCCAGCCAC
				319	1467	1486	TCATGGCTGCAATGCCAGCC
42	1470	1489	GCATCATGGCTGCAATGCCA
				320	1472	1491	CAGCATCATGGCTGCAATGC
321	1474	1493	GACAGCATCATGGCTGCAAT
				322	1476	1495	CAGACAGCATCATGGCTGCA
43	1478	1497	GGCAGACAGCATCATGGCTG
				323	1480	1499	TCGGCAGACAGCATCATGGC
324	1482	1501	GCTCGGCAGACAGCATCATG
				325	1484	1503	CGGCTCGGCAGACAGCATCA
326	1486	1505	TCCGGCTCGGCAGACAGCAT
				327	1500	1519	CGGCCAGGGTGAGCTCCGGC
328	1513	1532	CTCTGCCTCAACTCGGCCAG
				329	1515	1534	GTCTCTGCCTCAACTCGGCC
330	1517	1536	CAGTCTCTGCCTCAACTCGG
				331	1519	1538	ATCAGTCTCTGCCTCAACTC
332	1521	1540	GGATCAGTCTCTGCCTCAAC
				333	1523	1542	GTGGATCAGTCTCTGCCTCA
334	1525	1544	AAGTGGATCAGTCTCTGCCT
				44	1526	1545	GAAGTGGATCAGTCTCTGCC
335	1528	1547	GAGAAGTGGATCAGTCTCTG
				336	1530	1549	CAGAGAAGTGGATCAGTCTC
337	1532	1551	GGCAGAGAAGTGGATCAGTC
				45	1534	1553	TTGGCAGAGAAGTGGATCAG
338	1536	1555	CTTTGGCAGAGAAGTGGATC
				46	1539	1558	CATCTTTGGCAGAGAAGTGG
339	1541	1560	GACATCTTTGGCAGAGAAGT
				340	1543	1562	ATGACATCTTTGGCAGAGAA
47	1545	1564	TGATGACATCTTTGGCAGAG
				341	1547	1566	ATTGATGACATCTTTGGCAG
342	1549	1568	TCATTGATGACATCTTTGGC
				48	1552	1571	GCCTCATTGATGACATCTTT
343	1554	1573	AGGCCTCATTGATGACATCT

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				344	1556	1575	CCAGGCCTCATTGATGACAT
345	1558	1577	AACCAGGCCTCATTGATGAC
				346	1560	1579	GGAACCAGGCCTCATTGATG
347	1561	1580	GGGAACCAGGCCTCATTGAT
				348	1562	1581	AGGGAACCAGGCCTCATTGA
349	1563	1582	CAGGGAACCAGGCCTCATTG
				49	1564	1583	TCAGGGAACCAGGCCTCATT
49	1564	1583	TCAGGGAACCAGGCCTCATT
				350	1565	1584	CTCAGGGAACCAGGCCTCAT
351	1566	1585	CCTCAGGGAACCAGGCCTCA
				352	1567	1586	TCCTCAGGGAACCAGGCCTC
353	1568	1587	GTCCTCAGGGAACCAGGCCT
				50	1569	1588	GGTCCTCAGGGAACCAGGCC
354	1570	1589	TGGTCCTCAGGGAACCAGGC
				355	1571	1590	CTGGTCCTCAGGGAACCAGG
356	1572	1591	GCTGGTCCTCAGGGAACCAG
				357	1573	1592	CGCTGGTCCTCAGGGAACCA
87	1576	1595	ACCCGCTGGTCCTCAGGGAA
				358	1578	1597	GTACCCGCTGGTCCTCAGGG
359	1580	1599	CAGTACCCGCTGGTCCTCAG
				51	1583	1602	GGTCAGTACCCGCTGGTCCT
119	1605	1624	GCAGGGCGGCCACCAGGTTG
				360	1628	1647	ACCTGCCCCATGGGTGCTGG
52	1640	1659	AAACAGCTGCCAACCTGCCC
				361	1642	1661	CAAAACAGCTGCCAACCTGC
53	1645	1664	CTGCAAAACAGCTGCCAACC
				362	1647	1666	TCCTGCAAAACAGCTGCCAA
363	1649	1668	AGTCCTGCAAAACAGCTGCC
				364	1660	1679	GCTGACCATACAGTCCTGCA
365	1672	1691	GGCCCCGAGTGTGCTGACCA
				54	1675	1694	GTAGGCCCCGAGTGTGCTGA
366	1677	1696	GTGTAGGCCCCGAGTGTGCT
				367	1679	1698	CCGTGTAGGCCCCGAGTGTG
368	1681	1700	ATCCGTGTAGGCCCCGAGTG
				369	1683	1702	CCATCCGTGTAGGCCCCGAG
370	1685	1704	GGCCATCCGTGTAGGCCCCG
				371	1687	1706	GTGGCCATCCGTGTAGGCCC
372	1735	1754	CTGGAGCAGCTCAGCAGCTC
				460	1735	1748	CAGCTCAGCAGCTC
373	1737	1756	AACTGGAGCAGCTCAGCAGC
				55	1740	1759	AGAAACTGGAGCAGCTCAGC
374	1742	1761	GGAGAAACTGGAGCAGCTCA
				375	1744	1763	CTGGAGAAACTGGAGCAGCT
56	1746	1765	TCCTGGAGAAACTGGAGCAG
				57	1812	1831	CGTTGTGGGCCCGGCAGACC
376	1849	1868	CACCTGGCAATGGCGTAGAC
				377	1850	1869	GCACCTGGCAATGGCGTAGA
378	1851	1870	AGCACCTGGCAATGGCGTAG

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5-3 ')
				379	1852	1871	CAGCACCTGGCAATGGCGTA
380	1853	1872	GCAGCACCTGGCAATGGCGT
				381	1854	1873	GGCAGCACCTGGCAATGGCG
382	1855	1874	AGGCAGCACCTGGCAATGGC
				383	1856	1875	CAGGCAGCACCTGGCAATGG
384	1857	1876	GCAGGCAGCACCTGGCAATG
				58	1858	1877	AGCAGGCAGCACCTGGCAAT
385	1859	1878	TAGCAGGCAGCACCTGGCAA
				386	1860	1879	GTAGCAGGCAGCACCTGGCA
387	1905	1924	TGGCCTCAGCTGGTGGAGCT
				388	1915	1934	GTCCCCATGCTGGCCTCAGC
389	1916	1935	GGTCCCCATGCTGGCCTCAG
				390	1917	1936	GGGTCCCCATGCTGGCCTCA
391	1918	1937	CGGGTCCCCATGCTGGCCTC
				392	1919	1938	ACGGGTCCCCATGCTGGCCT
59	1920	1939	CACGGGTCCCCATGCTGGCC
				59	1920	1939	CACGGGTCCCCATGCTGGCC
393	1921	1940	ACACGGGTCCCCATGCTGGC
				394	1922	1941	GACACGGGTCCCCATGCTGG
395	1923	1942	GGACACGGGTCCCCATGCTG
				396	1924	1943	TGGACACGGGTCCCCATGCT
397	1925	1944	GTGGACACGGGTCCCCATGC
				398	1926	1945	AGTGGACACGGGTCCCCATG
399	1927	1946	CAGTGGACACGGGTCCCCAT
				400	1928	1947	GCAGTGGACACGGGTCCCCA
401	1929	1948	GGCAGTGGACACGGGTCCCC
				402	1930	1949	TGGCAGTGGACACGGGTCCC
403	1931	1950	GTGGCAGTGGACACGGGTCC
				404	1932	1951	GGTGGCAGTGGACACGGGTC
405	1933	1952	TGGTGGCAGTGGACACGGGT
				406	1936	1955	TGTTGGTGGCAGTGGACACG
407	1962	1981	AGCTGCAGCCTGTGAGGACG
				408	1990	2009	GTGCCAAGGTCCTCCACCTC
409	2010	2029	TCAGCACAGGCGGCTTGTGG
				410	2040	2059	CCACGCACTGGTTGGGCTGA
60	2100	2119	CTTTGCATTCCAGACCTGGG
				411	2101	2120	ACTTTGCATTCCAGACCTGG
412	2102	2121	GACTTTGCATTCCAGACCTG
				413	2103	2122	TGACTTTGCATTCCAGACCT
414	2104	2123	TTGACTTTGCATTCCAGACC
				61	2105	2124	CTTGACTTTGCATTCCAGAC
415	2107	2126	TCCTTGACTTTGCATTCCAG
				416	2120	2139	CGGGATTCCATGCTCCTTGA
417	2150	2169	GCAGGCCACGGTCACCTGCT
				418	2187	2206	GGAGGGCACTGCAGCCAGTC
419	2305	2324	CAGATGGCAACGGCTGTCAC
				420	2306	2325	GCAGATGGCAACGGCTGTCA
421	2307	2326	AGCAGATGGCAACGGCTGTC

SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Sequence (5 '-3 ')
				422	2308	2327	CAGCAGATGGCAACGGCTGT
423	2309	2328	GCAGCAGATGGCAACGGCTG
				62	2310	2329	GGCAGCAGATGGCAACGGCT
424	2311	2330	CGGCAGCAGATGGCAACGGC
				425	2312	2331	CCGGCAGCAGATGGCAACGG
426	2313	2332	TCCGGCAGCAGATGGCAACG
				427	2314	2333	CTCCGGCAGCAGATGGCAAC
428	2315	2334	GCTCCGGCAGCAGATGGCAA
				429	2325	2344	CCAGGTGCCGGCTCCGGCAG
430	2335	2354	GAGGCCTGCGCCAGGTGCCG
				154	2410	2429	TTTTAAAGCTCAGCCCCAGC
63	2415	2434	AACCATTTTAAAGCTCAGCC
				64	2504	2523	TCAAGGGCCAGGCCAGCAGC
65	2509	2528	CCCACTCAAGGGCCAGGCCA
				122	2582	2601	GGAGGGAGCTTCCTGGCACC
66	2597	2616	ATGCCCCACAGTGAGGGAGG
				67	2606	2625	AATGGTGAAATGCCCCACAG
153	2649	2668	TTGGGAGCAGCTGGCAGCAC
				68	2750	2769	CATGGGAAGAATCCTGCCTC
431	2828	2847	ATGAGGGCCATCAGCACCTT
				432	2829	2848	GATGAGGGCCATCAGCACCT
433	2830	2849	AGATGAGGGCCATCAGCACC
				434	2831	2850	GAGATGAGGGCCATCAGCAC
69	2832	2851	GGAGATGAGGGCCATCAGCA
				435	2833	2852	TGGAGATGAGGGCCATCAGC
436	2834	2853	CTGGAGATGAGGGCCATCAG
				437	2835	2854	GCTGGAGATGAGGGCCATCA
438	2836	2855	AGCTGGAGATGAGGGCCATC
				461	2877	2890	TTAATCAGGGAGCC
70	2900	2919	TAGATGCCATCCAGAAAGCT
				439	2902	2921	GCTAGATGCCATCCAGAAAG
440	2903	2922	GGCTAGATGCCATCCAGAAA
				441	2904	2923	TGGCTAGATGCCATCCAGAA
442	2905	2924	CTGGCTAGATGCCATCCAGA
				71	2906	2925	TCTGGCTAGATGCCATCCAG
443	2907	2926	CTCTGGCTAGATGCCATCCA
				444	2908	2927	CCTCTGGCTAGATGCCATCC
445	2909	2928	GCCTCTGGCTAGATGCCATC
				446	2910	2929	AGCCTCTGGCTAGATGCCAT
72	2983	3002	GGCATAGAGCAGAGTAAAGG
				73	2988	3007	AGCCTGGCATAGAGCAGAGT
135	2994	3013	TAGCACAGCCTGGCATAGAG
				112	3227	3246	GAAGAGGCTTGGCTTCAGAG
74	3233	3252	AAGTAAGAAGAGGCTTGGCT
				75	3437	3456	GCTCAAGGAGGGACAGTTGT
76	3472	3491	AAAGATAAATGTCTGCTTGC
				77	3477	3496	ACCCAAAAGATAAATGTCTG
78	3543	3562	TCTTCAAGTTACAAAAGCAA
				99	3550	3569	ATAAATATCTTCAAGTTACA

In certain embodiments, breach polymers antisense compounds target PCSK9 nucleic acid.In some such embodiment, breach polymers antisense compounds target SEQ ID NO:1.In some such embodiment, illustrative nucleotide sequence has 5-10-5 breach polymers motif in the table 1.Table 2 illustration the breach polymers antisense compounds of target SEQ ID NO:1, it has the 5-10-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate (phosphorthioate) between nucleosides, and cytidine is the 5-methylcytidine.

Table 2: the breach polymers antisense compounds of target SEQ ID NO:1 with 5-10-5 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							395149	5-10-5	4	135	154	0	GCGCGGAATCCTGGCTGGGA
395150	5-10-5	5	242	261	0	GAGGAGACCTAGAGGCCGTG
							395151	5-10-5	6	300	319	0	AGGACCGCCTGGAGCTGACG
395152	5-10-5	7	410	429	0	ACGCAAGGCTAGCACCAGCT
							399793	5-10-5	8	417	436	0	CCTCGGAACGCAAGGCTAGC
395153	5-10-5	9	480	499	0	CCTTGGCGCAGCGGTGGAAG
							395154	5-10-5	10	561	580	0	GGCGGGCAGTGCGCTCTGAC
395155	5-10-5	11	600	619	0	TGGTGAGGTATCCCCGGCGG
							399794	5-10-5	12	606	625	0	GGATCTTGGTGAGGTATCCC
399795	5-10-5	13	615	634	0	AGACATGCAGGATCTTGGTG
							395156	5-10-5	14	620	639	0	ATGGAAGACATGCAGGATCT
395157	5-10-5	15	646	665	0	TTCACCAGGAAGCCAGGAAG
							399796	5-10-5	16	651	670	0	TCATCTTCACCAGGAAGCCA
395158	5-10-5	17	705	724	0	CCTCGATGTAGTCGACATGG
							395159	5-10-5	18	785	804	0	GTATTCATCCGCCCGGTACC
395160	5-10-5	19	835	854	0	CTGGTGTCTAGGAGATACAC
							399797	5-10-5	20	840	859	0	GTATGCTGGTGTCTAGGAGA
395161	5-10-5	21	860	879	0	GATTTCCCGGTGGTCACTCT
							399798	5-10-5	22	866	885	0	GCCCTCGATTTCCCGGTGGT
399799	5-10-5	23	880	899	0	GTGACCATGACCCTGCCCTC
							395162	5-10-5	24	890	909	0	CTCGAAGTCGGTGACCATGA
395163	5-10-5	25	923	942	0	GTGGAAGCGGGTCCCGTCCT
							395164	5-10-5	26	970	989	0	ACCCCTGCCAGGTGGGTGCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							399800	5-10-5	27	975	994	0	TGACCACCCCTGCCAGGTGG
395165	5-10-5	28	1004	1023	0	ACCCTTGGCCACGCCGGCAT
							395166	5-10-5	29	1040	1059	0	TTGGCAGTTGAGCACGCGCA
399801	5-10-5	30	1045	1064	0	TTCCCTTGGCAGTTGAGCAC
							395167	5-10-5	31	1077	1096	0	CCAGGCCTATGAGGGTGCCG
395168	5-10-5	32	1098	1117	0	GCTGGCTTTTCCGAATAAAC
							395169	5-10-5	33	1210	1229	0	GTGACCAGCACGACCCCAGC
395170	5-10-5	149	1297	1316	0	TGGGCATTGGTGGCCCCAAC
							395171	5-10-5	34	1326	1345	0	CCAAAGTCCCCAGGGTCACC
395172	5-10-5	128	1330	1349	0	GTCCCCAAAGTCCCCAGGGT
							399802	5-10-5	35	1335	1354	0	AGTTGGTCCCCAAAGTCCCC
395173	5-10-5	36	1340	1359	0	GCCAAAGTTGGTCCCCAAAG
							399803	5-10-5	37	1352	1371	0	GTCCACACAGCGGCCAAAGT
395174	5-10-5	38	1361	1380	0	GGCAAAGAGGTCCACACAGC
							395175	5-10-5	39	1389	1408	0	TGGAGGCACCAATGATGTCC
399804	5-10-5	40	1400	1419	0	GCTGCAGTCGCTGGAGGCAC
							399805	5-10-5	41	1411	1430	0	ACAAAGCAGGTGCTGCAGTC
395176	5-10-5	101	1465	1484	0	ATGGCTGCAATGCCAGCCAC
							399806	5-10-5	42	1470	1489	0	GCATCATGGCTGCAATGCCA
399807	5-10-5	43	1478	1497	0	GGCAGACAGCATCATGGCTG
							399808	5-10-5	44	1526	1545	0	GAAGTGGATCAGTCTCTGCC
395177	5-10-5	45	1534	1553	0	TTGGCAGAGAAGTGGATCAG
							399809	5-10-5	46	1539	1558	0	CATCTTTGGCAGAGAAGTGG
399810	5-10-5	47	1545	1564	0	TGATGACATCTTTGGCAGAG
							399811	5-10-5	48	1552	1571	0	GCCTCATTGATGACATCTTT
399812	5-10-5	49	1564	1583	0	TCAGGGAACCAGGCCTCATT
							395178	5-10-5	50	1569	1588	0	GGTCCTCAGGGAACCAGGCC
395179	5-10-5	87	1576	1595	0	ACCCGCTGGTCCTCAGGGAA
							399813	5-10-5	51	1583	1602	0	GGTCAGTACCCGCTGGTCCT
395180	5-10-5	119	1605	1624	0	GCAGGGCGGCCACCAGGTTG
							395181	5-10-5	52	1640	1659	0	AAACAGCTGCCAACCTGCCC
399814	5-10-5	53	1645	1664	0	CTGCAAAACAGCTGCCAACC
							395182	5-10-5	54	1675	1694	0	GTAGGCCCCGAGTGTGCTGA
399815	5-10-5	55	1740	1759	0	AGAAACTGGAGCAGCTCAGC
							399816	5-10-5	56	1746	1765	0	TCCTGGAGAAACTGGAGCAG
395183	5-10-5	57	1812	1831	0	CGTTGTGGGCCCGGCAGACC
							395184	5-10-5	58	1858	1877	0	AGCAGGCAGCACCTGGCAAT
395185	5-10-5	59	1920	1939	0	CACGGGTCCCCATGCTGGCC
							395186	5-10-5	60	2100	2119	0	CTTTGCATTCCAGACCTGGG
399817	5-10-5	61	2105	2124	0	CTTGACTTTGCATTCCAGAC
							395187	5-10-5	62	2310	2329	0	GGCAGCAGATGGCAACGGCT
395188	5-10-5	154	2410	2429	0	TTTTAAAGCTCAGCCCCAGC
							399818	5-10-5	63	2415	2434	0	AACCATTTTAAAGCTCAGCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:I	Mispairing	Sequence (5 '-3 ')
							395189	5-10-5	64	2504	2523	0	TCAAGGGCCAGGCCAGCAGC
399819	5-10-5	65	2509	2528	0	CCCACTCAAGGGCCAGGCCA
							399820	5-10-5	122	2582	2601	0	GGAGGGAGCTTCCTGGCACC
395190	5-10-5	66	2597	2616	0	ATGCCCCACAGTGAGGGAGG
							395191	5-10-5	67	2606	2625	0	AATGGTGAAATGCCCCACAG
395192	5-10-5	153	2649	2668	0	TTGGGAGCAGCTGGCAGCAC
							395193	5-10-5	68	2750	2769	0	CATGGGAAGAATCCTGCCTC
395194	5-10-5	69	2832	2851	0	GGAGATGAGGGCCATCAGCA
							395195	5-10-5	70	2900	2919	0	TAGATGCCATCCAGAAAGCT
399821	5-10-5	71	2906	2925	0	TCTGGCTAGATGCCATCCAG
							395196	5-10-5	72	2983	3002	0	GGCATAGAGCAGAGTAAAGG
399822	5-10-5	73	2988	3007	0	AGCCTGGCATAGAGCAGAGT
							399823	5-10-5	135	2994	3013	0	TAGCACAGCCTGGCATAGAG
395197	5-10-5	112	3227	3246	0	GAAGAGGCTTGGCTTCAGAG
							399824	5-10-5	74	3233	3252	0	AAGTAAGAAGAGGCTTGGCT
395198	5-10-5	75	3437	3456	0	GCTCAAGGAGGGACAGTTGT
							395199	5-10-5	76	3472	3491	0	AAAGATAAATGTCTGCTTGC
399825	5-10-5	77	3477	3496	0	ACCCAAAAGATAAATGTCTG
							395200	5-10-5	78	3543	3562	0	TCTTCAAGTTACAAAAGCAA
399826	5-10-5	99	3550	3569	0	ATAAATATCTTCAAGTTACA
							405861	5-10-5	162	406	425	0	AAGGCTAGCACCAGCTCCTC
405862	5-10-5	163	407	426	0	CAAGGCTAGCACCAGCTCCT
							405863	5-10-5	164	408	427	0	GCAAGGCTAGCACCAGCTCC
405864	5-10-5	165	409	428	0	CGCAAGGCTAGCACCAGCTC
							405865	5-10-5	166	411	430	0	AACGCAAGGCTAGCACCAGC
405866	5-10-5	167	412	431	0	GAACGCAAGGCTAGCACCAG
							405867	5-10-5	168	413	432	0	GGAACGCAAGGCTAGCACCA
405868	5-10-5	169	414	433	0	CGGAACGCAAGGCTAGCACC
							405869	5-10-5	218	862	881	0	TCGATTTCCCGGTGGTCACT
405870	5-10-5	219	863	882	0	CTCGATTTCCCGGTGGTCAC
							405871	5-10-5	220	864	883	0	CCTCGATTTCCCGGTGGTCA
405872	5-10-5	221	865	884	0	CCCTCGATTTCCCGGTGGTC
							405873	5-10-5	222	867	886	0	TGCCCTCGATTTCCCGGTGG
405874	5-10-5	223	868	887	0	CTGCCCTCGATTTCCCGGTG
							405875	5-10-5	224	869	888	0	CCTGCCCTCGATTTCCCGGT
405876	5-10-5	225	870	889	0	CCCTGCCCTCGATTTCCCGG
							405877	5-10-5	246	1000	1019	0	TTGGCCACGCCGGCATCCCG
405878	5-10-5	247	1001	1020	0	CTTGGCCACGCCGGCATCCC
							405879	5-10-5	248	1002	1021	0	CCTTGGCCACGCCGGCATCC
405880	5-10-5	249	1003	1022	0	CCCTTGGCCACGCCGGCATC
							405881	5-10-5	250	1005	1024	0	CACCCTTGGCCACGCCGGCA
405882	5-10-5	251	1006	1025	0	GCACCCTTGGCCACGCCGGC
							405883	5-10-5	252	1007	1026	0	GGCACCCTTGGCCACGCCGG
405884	5-10-5	253	1008	1027	0	TGGCACCCTTGGCCACGCCG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							405885	5-10-5	346	1560	1579	0	GGAACCAGGCCTCATTGATG
405886	5-10-5	347	1561	1580	0	GGGAACCAGGCCTCATTGAT
							405887	5-10-5	348	1562	1581	0	AGGGAACCAGGCCTCATTGA
405888	5-10-5	349	1563	1582	0	CAGGGAACCAGGCCTCATTG
							405889	5-10-5	350	1565	1584	0	CTCAGGGAACCAGGCCTCAT
405890	5-10-5	351	1566	1585	0	CCTCAGGGAACCAGGCCTCA
							405891	5-10-5	352	1567	1586	0	TCCTCAGGGAACCAGGCCTC
405892	5-10-5	353	1568	1587	0	GTCCTCAGGGAACCAGGCCT
							405893	5-10-5	431	2828	2847	0	ATGAGGGCCATCAGCACCTT
405894	5-10-5	432	2829	2848	0	GATGAGGGCCATCAGCACCT
							405895	5-10-5	433	2830	2849	0	AGATGAGGGCCATCAGCACC
405896	5-10-5	434	2831	2850	0	GAGATGAGGGCCATCAGCAC
							405897	5-10-5	435	2833	2852	0	TGGAGATGAGGGCCATCAGC
405898	5-10-5	436	2834	2853	0	CTGGAGATGAGGGCCATCAG
							405899	5-10-5	437	2835	2854	0	GCTGGAGATGAGGGCCATCA
405900	5-10-5	438	2836	2855	0	AGCTGGAGATGAGGGCCATC
							405901	5-10-5	439	2902	2921	0	GCTAGATGCCATCCAGAAAG
405902	5-10-5	440	2903	2922	0	GGCTAGATGCCATCCAGAAA
							405903	5-10-5	441	2904	2923	0	TGGCTAGATGCCATCCAGAA
405904	5-10-5	442	2905	2924	0	CTGGCTAGATGCCATCCAGA
							405905	5-10-5	443	2907	2926	0	CTCTGGCTAGATGCCATCCA
405906	5-10-5	444	2908	2927	0	CCTCTGGCTAGATGCCATCC
							405907	5-10-5	445	2909	2928	0	GCCTCTGGCTAGATGCCATC
405908	5-10-5	446	2910	2929	0	AGCCTCTGGCTAGATGCCAT
							405909	5-10-5	267	1100	1119	0	CAGCTGGCTTTTCCGAATAA
405910	5-10-5	268	1102	1121	0	ACCAGCTGGCTTTTCCGAAT
							405911	5-10-5	269	1104	1123	0	GGACCAGCTGGCTTTTCCGA
405912	5-10-5	270	1108	1127	0	GGCTGGACCAGCTGGCTTTT
							405913	5-10-5	275	1212	1231	0	CGGTGACCAGCACGACCCCA
405914	5-10-5	276	1214	1233	0	AGCGGTGACCAGCACGACCC
							405915	5-10-5	277	1216	1235	0	GCAGCGGTGACCAGCACGAC
405916	5-10-5	278	1218	1237	0	CGGCAGCGGTGACCAGCACG
							405917	5-10-5	280	1222	1241	0	TTGCCGGCAGCGGTGACCAG
405918	5-10-5	281	1224	1243	0	AGTTGCCGGCAGCGGTGACC
							405919	5-10-5	282	1226	1245	0	GAAGTTGCCGGCAGCGGTGA
405920	5-10-5	283	1228	1247	0	CGGAAGTTGCCGGCAGCGGT
							405921	5-10-5	284	1230	1249	0	CCCGGAAGTTGCCGGCAGCG
405922	5-10-5	285	1232	1251	0	GTCCCGGAAGTTGCCGGCAG
							405923	5-10-5	288	1295	1314	0	GGCATTGGTGGCCCCAACTG
405924	5-10-5	290	1318	1337	0	CCCAGGGTCACCGGCTGGTC
							405925	5-10-5	292	1322	1341	0	AGTCCCCAGGGTCACCGGCT
405926	5-10-5	293	1324	1343	0	AAAGTCCCCAGGGTCACCGG
							405927	5-10-5	294	1328	1347	0	CCCCAAAGTCCCCAGGGTCA
405928	5-10-5	295	1333	1352	0	TTGGTCCCCAAAGTCCCCAG
							405929	5-10-5	296	1337	1356	0	AAAGTTGGTCCCCAAAGTCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							405930	5-10-5	297	1342	1361	0	CGGCCAAAGTTGGTCCCCAA
405931	5-10-5	298	1344	1363	0	AGCGGCCAAAGTTGGTCCCC
							405932	5-10-5	299	1346	1365	0	ACAGCGGCCAAAGTTGGTCC
405933	5-10-5	300	1348	1367	0	ACACAGCGGCCAAAGTTGGT
							405934	5-10-5	301	1350	1369	0	CCACACAGCGGCCAAAGTTG
405935	5-10-5	302	1354	1373	0	AGGTCCACACAGCGGCCAAA
							405936	5-10-5	304	1358	1377	0	AAAGAGGTCCACACAGCGGC
405937	5-10-5	306	1387	1406	0	GAGGCACCAATGATGTCCTC
							405938	5-10-5	307	1391	1410	0	GCTGGAGGCACCAATGATGT
405939	5-10-5	308	1393	1412	0	TCGCTGGAGGCACCAATGAT
							405940	5-10-5	309	1395	1414	0	AGTCGCTGGAGGCACCAATG
405941	5-10-5	310	1397	1416	0	GCAGTCGCTGGAGGCACCAA
							405942	5-10-5	311	1402	1421	0	GTGCTGCAGTCGCTGGAGGC
405943	5-10-5	312	1404	1423	0	AGGTGCTGCAGTCGCTGGAG
							405944	5-10-5	314	1407	1426	0	AGCAGGTGCTGCAGTCGCTG
405945	5-10-5	315	1409	1428	0	AAAGCAGGTGCTGCAGTCGC
							405946	5-10-5	316	1413	1432	0	ACACAAAGCAGGTGCTGCAG
405947	5-10-5	317	1415	1434	0	TGACACAAAGCAGGTGCTGC
							405948	5-10-5	319	1467	1486	0	TCATGGCTGCAATGCCAGCC
405949	5-10-5	320	1472	1491	0	CAGCATCATGGCTGCAATGC
							405950	5-10-5	321	1474	1493	0	GACAGCATCATGGCTGCAAT
405951	5-10-5	322	1476	1495	0	CAGACAGCATCATGGCTGCA
							405952	5-10-5	323	1480	1499	0	TCGGCAGACAGCATCATGGC
405953	5-10-5	325	1484	1503	0	CGGCTCGGCAGACAGCATCA
							405954	5-10-5	326	1486	1505	0	TCCGGCTCGGCAGACAGCAT
405955	5-10-5	328	1513	1532	0	CTCTGCCTCAACTCGGCCAG
							405956	5-10-5	329	1515	1534	0	GTCTCTGCCTCAACTCGGCC
405957	5-10-5	330	1517	1536	0	CAGTCTCTGCCTCAACTCGG
							405958	5-10-5	331	1519	1538	0	ATCAGTCTCTGCCTCAACTC
405959	5-10-5	332	1521	1540	0	GGATCAGTCTCTGCCTCAAC
							405960	5-10-5	333	1523	1542	0	GTGGATCAGTCTCTGCCTCA
405961	5-10-5	334	1525	1544	0	AAGTGGATCAGTCTCTGCCT
							405962	5-10-5	335	1528	1547	0	GAGAAGTGGATCAGTCTCTG
405963	5-10-5	337	1532	1551	0	GGCAGAGAAGTGGATCAGTC
							405964	5-10-5	338	1536	1555	0	CTTTGGCAGAGAAGTGGATC
405965	5-10-5	339	1541	1560	0	GACATCTTTGGCAGAGAAGT
							405966	5-10-5	340	1543	1562	0	ATGACATCTTTGGCAGAGAA
405967	5-10-5	341	1547	1566	0	ATTGATGACATCTTTGGCAG
							405968	5-10-5	342	1549	1568	0	TCATTGATGACATCTTTGGC
405969	5-10-5	343	1554	1573	0	AGGCCTCATTGATGACATCT
							405970	5-10-5	344	1556	1575	0	CCAGGCCTCATTGATGACAT
405971	5-10-5	355	1571	1590	0	CTGGTCCTCAGGGAACCAGG
							405972	5-10-5	357	1573	1592	0	CGCTGGTCCTCAGGGAACCA
405973	5-10-5	358	1578	1597	0	GTACCCGCTGGTCCTCAGGG
							405974	5-10-5	359	1580	1599	0	CAGTACCCGCTGGTCCTCAG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							405975	5-10-5	361	1642	1661	0	CAAAACAGCTGCCAACCTGC
405976	5-10-5	362	1647	1666	0	TCCTGCAAAACAGCTGCCAA
							405977	5-10-5	363	1649	1668	0	AGTCCTGCAAAACAGCTGCC
405978	5-10-5	365	1672	1691	0	GGCCCCGAGTGTGCTGACCA
							405979	5-10-5	366	1677	1696	0	GTGTAGGCCCCGAGTGTGCT
405980	5-10-5	367	1679	1698	0	CCGTGTAGGCCCCGAGTGTG
							405981	5-10-5	368	1681	1700	0	ATCCGTGTAGGCCCCGAGTG
405982	5-10-5	370	1685	1704	0	GGCCATCCGTGTAGGCCCCG
							405983	5-10-5	371	1687	1706	0	GTGGCCATCCGTGTAGGCCC
405984	5-10-5	372	1735	1754	0	CTGGAGCAGCTCAGCAGCTC
							405985	5-10-5	373	1737	1756	0	AACTGGAGCAGCTCAGCAGC
405986	5-10-5	374	1742	1761	0	GGAGAAACTGGAGCAGCTCA
							405987	5-10-5	375	1744	1763	0	CTGGAGAAACTGGAGCAGCT
405988	5-10-5	381	1854	1873	0	GGCAGCACCTGGCAATGGCG
							405989	5-10-5	383	1856	1875	0	CAGGCAGCACCTGGCAATGG
405990	5-10-5	386	1860	1879	0	GTAGCAGGCAGCACCTGGCA
							405991	5-10-5	394	1922	1941	0	GACACGGGTCCCCATGCTGG
405992	5-10-5	396	1924	1943	0	TGGACACGGGTCCCCATGCT
							405993	5-10-5	398	1926	1945	0	AGTGGACACGGGTCCCCATG
405994	5-10-5	400	1928	1947	0	GCAGTGGACACGGGTCCCCA
							405995	5-10-5	402	1930	1949	0	TGGCAGTGGACACGGGTCCC
405996	5-10-5	412	2102	2121	0	GACTTTGCATTCCAGACCTG
							405997	5-10-5	415	2107	2126	0	TCCTTGACTTTGCATTCCAG
405998	5-10-5	426	2313	2332	0	TCCGGCAGCAGATGGCAACG
							405999	5-10-5	160	298	317	0	GACCGCCTGGAGCTGACGGT
406000	5-10-5	173	482	501	0	ATCCTTGGCGCAGCGGTGGA
							406001	5-10-5	174	484	503	0	GGATCCTTGGCGCAGCGGTG
406002	5-10-5	175	488	507	0	CCACGGATCCTTGGCGCAGC
							406003	5-10-5	178	555	574	0	CAGTGCGCTCTGACTGCGAG
406004	5-10-5	179	557	576	0	GGCAGTGCGCTCTGACTGCG
							406005	5-10-5	180	559	578	0	CGGGCAGTGCGCTCTGACTG
406006	5-10-5	181	562	581	0	CGGCGGGCAGTGCGCTCTGA
							406007	5-10-5	183	595	614	0	AGGTATCCCCGGCGGGCAGC
406008	5-10-5	188	602	621	0	CTTGGTGAGGTATCCCCGGC
							406009	5-10-5	190	604	623	0	ATCTTGGTGAGGTATCCCCG
406010	5-10-5	193	609	628	0	GCAGGATCTTGGTGAGGTAT
							406011	5-10-5	194	611	630	0	ATGCAGGATCTTGGTGAGGT
406012	5-10-5	195	613	632	0	ACATGCAGGATCTTGGTGAG
							406013	5-10-5	196	617	636	0	GAAGACATGCAGGATCTTGG
406014	5-10-5	199	648	667	0	TCTTCACCAGGAAGCCAGGA
							406015	5-10-5	200	653	672	0	ACTCATCTTCACCAGGAAGC
406016	5-10-5	201	655	674	0	CCACTCATCTTCACCAGGAA
							406017	5-10-5	203	659	678	0	GTCGCCACTCATCTTCACCA
406018	5-10-5	204	661	680	0	AGGTCGCCACTCATCTTCAC
							406019	5-10-5	205	663	682	0	GCAGGTCGCCACTCATCTTC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							406020	5-10-5	206	665	684	0	CAGCAGGTCGCCACTCATCT
406021	5-10-5	210	782	801	0	TTCATCCGCCCGGTACCGTG
							406022	5-10-5	211	784	803	0	TATTCATCCGCCCGGTACCG
406023	5-10-5	212	787	806	0	TGGTATTCATCCGCCCGGTA
							406024	5-10-5	213	789	808	0	GCTGGTATTCATCCGCCCGG
406025	5-10-5	216	832	851	0	GTGTCTAGGAGATACACCTC
							406026	5-10-5	217	837	856	0	TGCTGGTGTCTAGGAGATAC
406027	5-10-5	226	874	893	0	ATGACCCTGCCCTCGATTTC
							406028	5-10-5	227	876	895	0	CCATGACCCTGCCCTCGATT
406029	5-10-5	228	878	897	0	GACCATGACCCTGCCCTCGA
							406030	5-10-5	229	882	901	0	CGGTGACCATGACCCTGCCC
406031	5-10-5	230	884	903	0	GTCGGTGACCATGACCCTGC
							406032	5-10-5	232	888	907	0	CGAAGTCGGTGACCATGACC
406033	5-10-5	237	967	986	0	CCTGCCAGGTGGGTGCCATG
							406034	5-10-5	238	972	991	0	CCACCCCTGCCAGGTGGGTG
406035	5-10-5	239	977	996	0	GCTGACCACCCCTGCCAGGT
							406036	5-10-5	241	989	1008	0	GGCATCCCGGCCGCTGACCA
406037	5-10-5	242	992	1011	0	GCCGGCATCCCGGCCGCTGA
							406038	5-10-5	245	999	1018	0	TGGCCACGCCGGCATCCCGG
406039	5-10-5	257	1036	1055	0	CAGTTGAGCACGCGCAGGCT
							406040	5-10-5	258	1038	1057	0	GGCAGTTGAGCACGCGCAGG
406041	5-10-5	259	1042	1061	0	CCTTGGCAGTTGAGCACGCG
							406042	5-10-5	260	1047	1066	0	CCTTCCCTTGGCAGTTGAGC
406043	5-10-5	261	1051	1070	0	GTGCCCTTCCCTTGGCAGTT
							406044	5-10-5	262	1053	1072	0	CCGTGCCCTTCCCTTGGCAG
406045	5-10-5	266	1096	1115	0	TGGCTTTTCCGAATAAACTC
							408642	5-10-5	264	1076	1095	0	CAGGCCTATGAGGGTGCCGC
408653	5-10-5	354	1570	1589	0	TGGTCCTCAGGGAACCAGGC
							409126	5-10-5	447	1004	1023	1	ACCCTTGGTCACGCCGGCAT
410529	5-10-5	184	597	616	0	TGAGGTATCCCCGGCGGGCA
							410530	5-10-5	185	598	617	0	GTGAGGTATCCCCGGCGGGC
410531	5-10-5	186	599	618	0	GGTGAGGTATCCCCGGCGGG
							410532	5-10-5	187	601	620	0	TTGGTGAGGTATCCCCGGCG
410533	5-10-5	189	603	622	0	TCTTGGTGAGGTATCCCCGG
							410534	5-10-5	191	605	624	0	GATCTTGGTGAGGTATCCCC
410535	5-10-5	192	607	626	0	AGGATCTTGGTGAGGTATCC
							410536	5-10-5	243	997	1016	0	GCCACGCCGGCATCCCGGCC
410537	5-10-5	244	998	1017	0	GGCCACGCCGGCATCCCGGC
							410538	5-10-5	254	1009	1028	0	CTGGCACCCTTGGCCACGCC
410539	5-10-5	255	1010	1029	0	GCTGGCACCCTTGGCCACGC
							410540	5-10-5	356	1572	1591	0	GCTGGTCCTCAGGGAACCAG
410541	5-10-5	376	1849	1868	0	CACCTGGCAATGGCGTAGAC
							410542	5-10-5	377	1850	1869	0	GCACCTGGCAATGGCGTAGA
410543	5-10-5	378	1851	1870	0	AGCACCTGGCAATGGCGTAG
							410544	5-10-5	379	1852	1871	0	CAGCACCTGGCAATGGCGTA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410545	5-10-5	380	1853	1872	0	GCAGCACCTGGCAATGGCGT
410546	5-10-5	382	1855	1874	0	AGGCAGCACCTGGCAATGGC
							410547	5-10-5	384	1857	1876	0	GCAGGCAGCACCTGGCAATG
410548	5-10-5	385	1859	1878	0	TAGCAGGCAGCACCTGGCAA
							410549	5-10-5	388	1915	1934	0	GTCCCCATGCTGGCCTCAGC
410550	5-10-5	389	1916	1935	0	GGTCCCCATGCTGGCCTCAG
							410551	5-10-5	390	1917	1936	0	GGGTCCCCATGCTGGCCTCA
410552	5-10-5	391	1918	1937	0	CGGGTCCCCATGCTGGCCTC
							410553	5-10-5	392	1919	1938	0	ACGGGTCCCCATGCTGGCCT
410554	5-10-5	393	1921	1940	0	ACACGGGTCCCCATGCTGGC
							410555	5-10-5	395	1923	1942	0	GGACACGGGTCCCCATGCTG
410556	5-10-5	397	1925	1944	0	GTGGACACGGGTCCCCATGC
							410557	5-10-5	399	1927	1946	0	CAGTGGACACGGGTCCCCAT
410558	5-10-5	401	1929	1948	0	GGCAGTGGACACGGGTCCCC
							410559	5-10-5	403	1931	1950	0	GTGGCAGTGGACACGGGTCC
410560	5-10-5	404	1932	1951	0	GGTGGCAGTGGACACGGGTC
							410561	5-10-5	405	1933	1952	0	TGGTGGCAGTGGACACGGGT
410562	5-10-5	411	2101	2120	0	ACTTTGCATTCCAGACCTGG
							410563	5-10-5	413	2103	2122	0	TGACTTTGCATTCCAGACCT
410564	5-10-5	414	2104	2123	0	TTGACTTTGCATTCCAGACC
							410565	5-10-5	419	2305	2324	0	CAGATGGCAACGGCTGTCAC
410566	5-10-5	420	2306	2325	0	GCAGATGGCAACGGCTGTCA
							410567	5-10-5	421	2307	2326	0	AGCAGATGGCAACGGCTGTC
410568	5-10-5	422	2308	2327	0	CAGCAGATGGCAACGGCTGT
							410569	5-10-5	423	2309	2328	0	GCAGCAGATGGCAACGGCTG
410570	5-10-5	424	2311	2330	0	CGGCAGCAGATGGCAACGGC
							410571	5-10-5	425	2312	2331	0	CCGGCAGCAGATGGCAACGG
410572	5-10-5	427	2314	2333	0	CTCCGGCAGCAGATGGCAAC
							410573	5-10-5	428	2315	2334	0	GCTCCGGCAGCAGATGGCAA
410730	5-10-5	202	657	676	0	CGCCACTCATCTTCACCAGG
							410731	5-10-5	207	667	686	0	TCCAGCAGGTCGCCACTCAT
410732	5-10-5	214	791	810	0	GGGCTGGTATTCATCCGCCC
							410733	5-10-5	231	886	905	0	AAGTCGGTGACCATGACCCT
410734	5-10-5	279	1219	1238	0	CCGGCAGCGGTGACCAGCAC
							410735	5-10-5	291	1320	1339	0	TCCCCAGGGTCACCGGCTGG
410736	5-10-5	303	1356	1375	0	AGAGGTCCACACAGCGGCCA
							410737	5-10-5	313	1406	1425	0	GCAGGTGCTGCAGTCGCTGG
410738	5-10-5	324	1482	1501	0	GCTCGGCAGACAGCATCATG
							410739	5-10-5	336	1530	1549	0	CAGAGAAGTGGATCAGTCTC
410740	5-10-5	345	1558	1577	0	AACCAGGCCTCATTGATGAC
							410741	5-10-5	369	1683	1702	0	CCATCCGTGTAGGCCCCGAG
410742	5-10-5	159	294	313	0	GCCTGGAGCTGACGGTGCCC
							410743	5-10-5	170	421	440	0	TCCTCCTCGGAACGCAAGGC
410744	5-10-5	171	446	465	0	GTGCTCGGGTGCTTCGGCCA
							410745	5-10-5	172	466	485	0	TGGAAGGTGGCTGTGGTTCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410746	5-10-5	176	507	526	0	CGTAGGTGCCAGGCAACCTC
410747	5-10-5	177	545	564	0	TGACTGCGAGAGGTGGGTCT
							410748	5-10-5	182	591	610	0	ATCCCCGGCGGGCAGCCTGG
410749	5-10-5	197	628	647	0	AGAAGGCCATGGAAGACATG
							410750	5-10-5	198	638	657	0	GAAGCCAGGAAGAAGGCCAT
410751	5-10-5	208	685	704	0	GGCAACTTCAAGGCCAGCTC
							410752	5-10-5	209	724	743	0	GCAAAGACAGAGGAGTCCTC
410753	5-10-5	215	821	840	0	ATACACCTCCACCAGGCTGC
							410754	5-10-5	233	898	917	0	GGCACATTCTCGAAGTCGGT
410755	5-10-5	234	933	952	0	TGGCCTGTCTGTGGAAGCGG
							410756	5-10-5	235	960	979	0	GGTGGGTGCCATGACTGTCA
410757	5-10-5	240	985	1004	0	TCCCGGCCGCTGACCACCCC
							410758	5-10-5	256	1015	1034	0	CGCATGCTGGCACCCTTGGC
410759	5-10-5	263	1064	1083	0	GGTGCCGCTAACCGTGCCCT
							410760	5-10-5	265	1088	1107	0	CCGAATAAACTCCAGGCCTA
410761	5-10-5	271	1119	1138	0	GTGGCCCCACAGGCTGGACC
							410762	5-10-5	272	1132	1151	0	AGCAGCACCACCAGTGGCCC
410763	5-10-5	273	1154	1173	0	GCTGTACCCACCCGCCAGGG
							410764	5-10-5	274	1200	1219	0	CGACCCCAGCCCTCGCCAGG
410765	5-10-5	286	1273	1292	0	ATGACCTCGGGAGCTGAGGC
							410766	5-10-5	287	1283	1302	0	CCCAACTGTGATGACCTCGG
410767	5-10-5	289	1305	1324	0	GCTGGTCTCGGGCATTGGTG
							410768	5-10-5	305	1380	1399	0	CAATGATGTCCTCCCCTGGG
410769	5-10-5	318	1425	1444	0	TCCCACTCTGTGACACAAAG
							410770	5-10-5	327	1500	1519	0	CGGCCAGGGTGAGCTCCGGC
410771	5-10-5	360	1628	1647	0	ACCTGCCCCATGGGTGCTGG
							410772	5-10-5	364	1660	1679	0	GCTGACCATACAGTCCTGCA
410773	5-10-5	387	1905	1924	0	TGGCCTCAGCTGGTGGAGCT
							410774	5-10-5	406	1936	1955	0	TGTTGGTGGCAGTGGACACG
410775	5-10-5	407	1962	1981	0	AGCTGCAGCCTGTGAGGACG
							410776	5-10-5	408	1990	2009	0	GTGCCAAGGTCCTCCACCTC
410777	5-10-5	409	2010	2029	0	TCAGCACAGGCGGGTTGTGG
							410778	5-10-5	410	2040	2059	0	CCACGCACTGGCTGGGCCGA
410779	5-10-5	416	2120	2139	0	CGGGATTCCATGCTCCTTGA
							410780	5-10-5	417	2150	2169	0	GCAGGCCACGGTCACCTGCT
410781	5-10-5	418	2187	2206	0	GGAGGGCACTGCAGCCAGTC
							410782	5-10-5	429	2325	2344	0	CCAGGTGCCGGCTCCGGCAG
410783	5-10-5	430	2335	2354	0	GAGGCCTGCGCCAGGTGCCG

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:1 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 3-14-3 breach and widens motif in the table 1.Table 3 illustration the antisense compounds widened of the breach of target SEQ ID NO:1, it has the 3-14-3 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 3: the breach polymers antisense compounds of target SEQ ID NO:1 with 3-14-3 motif

Isis number	Motif	SEQ ID NO	5 ' target site to SEQ ID NO:1	3 ' target site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							399871	3-14-3	4	135	154	0	GCGCGGAATCCTGGCTGGGA
399872	3-14-3	5	242	261	0	GAGGAGACCTAGAGGCCGTG
							399873	3-14-3	6	300	319	0	AGGACCGCCTGGAGCTGACG
399874	3-14-3	7	410	429	0	ACGCAAGGCTAGCACCAGCT
							399949	3-14-3	8	417	436	0	CCTCGGAACGCAAGGCTAGC
399875	3-14-3	9	480	499	0	CCTTGGCGCAGCGGTGGAAG
							399876	3-14-3	10	561	580	0	GGCGGGCAGTGCGCTCTGAC
399877	3-14-3	11	600	619	0	TGGTGAGGTATCCCCGGCGG
							399950	3-14-3	12	606	625	0	GGATCTTGGTGAGGTATCCC
399951	3-14-3	13	615	634	0	AGACATGCAGGATCTTGGTG
							399878	3-14-3	14	620	639	0	ATGGAAGACATGCAGGATCT
399879	3-14-3	15	646	665	0	TTCACCAGGAAGCCAGGAAG
							399952	3-14-3	16	651	670	0	TCATCTTCACCAGGAAGCCA
399880	3-14-3	17	705	724	0	CCTCGATGTAGTCGACATGG
							399881	3-14-3	18	785	804	0	GTATTCATCCGCCCGGTACC
399882	3-14-3	19	835	854	0	CTGGTGTCTAGGAGATACAC
							399953	3-14-3	20	840	859	0	GTATGCTGGTGTCTAGGAGA
399883	3-14-3	21	860	879	0	GATTTCCCGGTGGTCACTCT
							399954	3-14-3	22	866	885	0	GCCCTCGATTTCCCGGTGGT
399955	3-14-3	23	880	899	0	GTGACCATGACCCTGCCCTC
							399884	3-14-3	24	890	909	0	CTCGAAGTCGGTGACCATGA
399885	3-14-3	25	923	942	0	GTGGAAGCGGGTCCCGTCCT
							399886	3-14-3	26	970	989	0	ACCCCTGCCAGGTGGGTGCC
399956	3-14-3	27	975	994	0	TGACCACCCCTGCCAGGTGG
							399887	3-14-3	28	1004	1023	0	ACCCTTGGCCACGCCGGCAT
399888	3-14-3	29	1040	1059	0	TTGGCAGTTGAGCACGCGCA
							399957	3-14-3	30	1045	1064	0	TTCCCTTGGCAGTTGAGCAC
399889	3-14-3	31	1077	1096	0	CCAGGCCTATGAGGGTGCCG
							399890	3-14-3	32	1098	1117	0	GCTGGCTTTTCCGAATAAAC
399891	3-14-3	33	1210	1229	0	GTGACCAGCACGACCCCAGC
							399892	3-14-3	149	1297	1316	0	TGGGCATTGGTGGCCCCAAC
399893	3-14-3	34	1326	1345	0	CCAAAGTCCCCAGGGTCACC
							399894	3-14-3	128	1330	1349	0	GTCCCCAAAGTCCCCAGGGT
399958	3-14-3	35	1335	1354	0	AGTTGGTCCCCAAAGTCCCC
							399895	3-14-3	36	1340	1359	0	GCCAAAGTTGGTCCCCAAAG
399959	3-14-3	37	1352	1371	0	GTCCACACAGCGGCCAAAGT
							399896	3-14-3	38	1361	1380	0	GGCAAAGAGGTCCACACAGC
399897	3-14-3	39	1389	1408	0	TGGAGGCACCAATGATGTCC
							399960	3-14-3	40	1400	1419	0	GCTGCAGTCGCTGGAGGCAC
399961	3-14-3	41	1411	1430	0	ACAAAGCAGGTGCTGCAGTC
							399898	3-14-3	101	1465	1484	0	ATGGCTGCAATGCCAGCCAC

Isis number	Motif	SEQ ID NO	5 ' target site to SEQ ID NO:1	3 ' target site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							399962	3-14-3	42	1470	1489	0	GCATCATGGCTGCAATGCCA
399963	3-14-3	43	1478	1497	0	GGCAGACAGCATCATGGCTG
							399964	3-14-3	44	1526	1545	0	GAAGTGGATCAGTCTCTGCC
399899	3-14-3	45	1534	1553	0	TTGGCAGAGAAGTGGATCAG
							399965	3-14-3	46	1539	1558	0	CATCTTTGGCAGAGAAGTGG
399966	3-14-3	47	1545	1564	0	TGATGACATCTTTGGCAGAG
							399967	3-14-3	48	1552	1571	0	GCCTCATTGATGACATCTTT
399968	3-14-3	49	1564	1583	0	TCAGGGAACCAGGCCTCATT
							399900	3-14-3	50	1569	1588	0	GGTCCTCAGGGAACCAGGCC
399901	3-14-3	87	1576	1595	0	ACCCGCTGGTCCTCAGGGAA
							399969	3-14-3	51	1583	1602	0	GGTCAGTACCCGCTGGTCCT
399902	3-14-3	119	1605	1624	0	GCAGGGCGGCCACCAGGTTG
							399903	3-14-3	52	1640	1659	0	AAACAGCTGCCAACCTGCCC
399970	3-14-3	53	1645	1664	0	CTGCAAAACAGCTGCCAACC
							399904	3-14-3	54	1675	1694	0	GTAGGCCCCGAGTGTGCTGA
399971	3-14-3	55	1740	1759	0	AGAAACTGGAGCAGCTCAGC
							399972	3-14-3	56	1746	1765	0	TCCTGGAGAAACTGGAGCAG
399905	3-14-3	57	1812	1831	0	CGTTGTGGGCCCGGCAGACC
							399906	3-14-3	58	1858	1877	0	AGCAGGCAGCACCTGGCAAT
399907	3-14-3	59	1920	1939	0	CACGGGTCCCCATGCTGGCC
							399908	3-14-3	60	2100	2119	0	CTTTGCATTCCAGACCTGGG
399973	3-14-3	61	2105	2124	0	CTTGACTTTGCATTCCAGAC
							399909	3-14-3	62	2310	2329	0	GGCAGCAGATGGCAACGGCT
399910	3-14-3	154	2410	2429	0	TTTTAAAGCTCAGCCCCAGC
							399974	3-14-3	63	2415	2434	0	AACCATTTTAAAGCTCAGCC
399911	3-14-3	64	2504	2523	0	TCAAGGGCCAGGCCAGCAGC
							399975	3-14-3	65	2509	2528	0	CCCACTCAAGGGCCAGGCCA
399976	3-14-3	122	2582	2601	0	GGAGGGAGCTTCCTGGCACC
							399912	3-14-3	66	2597	2616	0	ATGCCCCACAGTGAGGGAGG
399913	3-14-3	67	2606	2625	0	AATGGTGAAATGCCCCACAG
							399914	3-14-3	153	2649	2668	0	TTGGGAGCAGCTGGCAGCAC
399915	3-14-3	68	2750	2769	0	CATGGGAAGAATCCTGCCTC
							399916	3-14-3	69	2832	2851	0	GGAGATGAGGGCCATCAGCA
399917	3-14-3	70	2900	2919	0	TAGATGCCATCCAGAAAGCT
							399977	3-14-3	71	2906	2925	0	TCTGGCTAGATGCCATCCAG
399918	3-14-3	72	2983	3002	0	GGCATAGAGCAGAGTAAAGG
							399978	3-14-3	73	2988	3007	0	AGCCTGGCATAGAGCAGAGT
399979	3-14-3	135	2994	3013	0	TAGCACAGCCTGGCATAGAG
							399919	3-14-3	112	3227	3246	0	GAAGAGGCTTGGCTTCAGAG
399980	3-14-3	74	3233	3252	0	AAGTAAGAAGAGGCTTGGCT
							399920	3-14-3	75	3437	3456	0	GCTCAAGGAGGGACAGTTGT
399921	3-14-3	76	3472	3491	0	AAAGATAAATGTCTGCTTGC
							399981	3-14-3	77	3477	3496	0	ACCCAAAAGATAAATGTCTG
399922	3-14-3	78	3543	3562	0	TCTTCAAGTTACAAAAGCAA
							399982	3-14-3	99	3550	3569	0	ATAAATATCTTCAAGTTACA
410574	3-14-3	184	597	616	0	TGAGGTATCCCCGGCGGGCA
							410575	3-14-3	185	598	617	0	GTGAGGTATCCCCGGCGGGC
410576	3-14-3	186	599	618	0	GGTGAGGTATCCCCGGCGGG
							410577	3-14-3	187	601	620	0	TTGGTGAGGTATCCCCGGCG

Isis number	Motif	SEQ ID NO	5 ' target site to SEQ ID NO:1	3 ' target site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410578	3-14-3	188	602	621	0	CTTGGTGAGGTATCCCCGGC
410579	3-14-3	189	603	622	0	TCTTGGTGAGGTATCCCCGG
							410580	3-14-3	190	604	623	0	ATCTTGGTGAGGTATCCCCG
410581	3-14-3	191	605	624	0	GATCTTGGTGAGGTATCCCC
							410582	3-14-3	192	607	626	0	AGGATCTTGGTGAGGTATCC
405604	3-14-3	236	963	982	0	CCAGGTGGGTGCCATGACTG
							410583	3-14-3	243	997	1016	0	GCCACGCCGGCATCCCGGCC
410584	3-14-3	244	998	1017	0	GGCCACGCCGGCATCCCGGC
							410585	3-14-3	245	999	1018	0	TGGCCACGCCGGCATCCCGG
410586	3-14-3	246	1000	1019	0	TTGGCCACGCCGGCATCCCG
							410587	3-14-3	247	1001	1020	0	CTTGGCCACGCCGGCATCCC
410588	3-14-3	248	1002	1021	0	CCTTGGCCACGCCGGCATCC
							410589	3-14-3	249	1003	1022	0	CCCTTGGCCACGCCGGCATC
410590	3-14-3	250	1005	1024	0	CACCCTTGGCCACGCCGGCA
							410591	3-14-3	251	1006	1025	0	GCACCCTTGGCCACGCCGGC
410592	3-14-3	252	1007	1026	0	GGCACCCTTGGCCACGCCGG
							410593	3-14-3	253	1008	1027	0	TGGCACCCTTGGCCACGCCG
410594	3-14-3	254	1009	1028	0	CTGGCACCCTTGGCCACGCC
							410595	3-14-3	255	1010	1029	0	GCTGGCACCCTTGGCCACGC
410596	3-14-3	348	1562	1581	0	AGGGAACCAGGCCTCATTGA
							410597	3-14-3	349	1563	1582	0	CAGGGAACCAGGCCTCATTG
410598	3-14-3	350	1565	1584	0	CTCAGGGAACCAGGCCTCAT
							410599	3-14-3	351	1566	1585	0	CCTCAGGGAACCAGGCCTCA
410600	3-14-3	352	1567	1586	0	TCCTCAGGGAACCAGGCCTC
							410601	3-14-3	353	1568	1587	0	GTCCTCAGGGAACCAGGCCT
410602	3-14-3	354	1570	1589	0	TGGTCCTCAGGGAACCAGGC
							410603	3-14-3	355	1571	1590	0	CTGGTCCTCAGGGAACCAGG
410604	3-14-3	356	1572	1591	0	GCTGGTCCTCAGGGAACCAG
							405641	3-14-3	373	1737	1756	0	AACTGGAGCAGCTCAGCAGC
410605	3-14-3	376	1849	1868	0	CACCTGGCAATGGCGTAGAC
							410606	3-14-3	377	1850	1869	0	GCACCTGGCAATGGCGTAGA
410607	3-14-3	378	1851	1870	0	AGCACCTGGCAATGGCGTAG
							410608	3-14-3	379	1852	1871	0	CAGCACCTGGCAATGGCGTA
410609	3-14-3	380	1853	1872	0	GCAGCACCTGGCAATGGCGT
							410610	3-14-3	381	1854	1873	0	GGCAGCACCTGGCAATGGCG
410611	3-14-3	382	1855	1874	0	AGGCAGCACCTGGCAATGGC
							410612	3-14-3	383	1856	1875	0	CAGGCAGCACCTGGCAATGG
410613	3-14-3	384	1857	1876	0	GCAGGCAGCACCTGGCAATG
							410614	3-14-3	385	1859	1878	0	TAGCAGGCAGCACCTGGCAA
410615	3-14-3	388	1915	1934	0	GTCCCCATGCTGGCCTCAGC
							410616	3-14-3	389	1916	1935	0	GGTCCCCATGCTGGCCTCAG
410617	3-14-3	390	1917	1936	0	GGGTCCCCATGCTGGCCTCA
							410618	3-14-3	391	1918	1937	0	CGGGTCCCCATGCTGGCCTC
410619	3-14-3	392	1919	1938	0	ACGGGTCCCCATGCTGGCCT
							410620	3-14-3	393	1921	1940	0	ACACGGGTCCCCATGCTGGC
410621	3-14-3	394	1922	1941	0	GACACGGGTCCCCATGCTGG
							410622	3-14-3	395	1923	1942	0	GGACACGGGTCCCCATGCTG
410623	3-14-3	396	1924	1943	0	TGGACACGGGTCCCCATGCT
							410624	3-14-3	397	1925	1944	0	GTGGACACGGGTCCCCATGC

Isis number	Motif	SEQ ID NO	5 ' target site to SEQ ID NO:1	3 ' target site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410625	3-14-3	398	1926	1945	0	AGTGGACACGGGTCCCCATG
410626	3-14-3	399	1927	1946	0	CAGTGGACACGGGTCCCCAT
							410627	3-14-3	400	1928	1947	0	GCAGTGGACACGGGTCCCCA
410628	3-14-3	401	1929	1948	0	GGCAGTGGACACGGGTCCCC
							410629	3-14-3	402	1930	1949	0	TGGCAGTGGACACGGGTCCC
410630	3-14-3	403	1931	1950	0	GTGGCAGTGGACACGGGTCC
							410631	3-14-3	404	1932	1951	0	GGTGGCAGTGGACACGGGTC
410632	3-14-3	405	1933	1952	0	TGGTGGCAGTGGACACGGGT
							410633	3-14-3	411	2101	2120	0	ACTTTGCATTCCAGACCTGG
410634	3-14-3	412	2102	2121	0	GACTTTGCATTCCAGACCTG
							410635	3-14-3	413	2103	2122	0	TGACTTTGCATTCCAGACCT
410636	3-14-3	414	2104	2123	0	TTGACTTTGCATTCCAGACC
							410637	3-14-3	419	2305	2324	0	CAGATGGCAACGGCTGTCAC
410638	3-14-3	420	2306	2325	0	GCAGATGGCAACGGCTGTCA
							410639	3-14-3	421	2307	2326	0	AGCAGATGGCAACGGCTGTC
410640	3-14-3	422	2308	2327	0	CAGCAGATGGCAACGGCTGT
							410641	3-14-3	423	2309	2328	0	GCAGCAGATGGCAACGGCTG
410642	3-14-3	424	2311	2330	0	CGGCAGCAGATGGCAACGGC
							410643	3-14-3	425	2312	2331	0	CCGGCAGCAGATGGCAACGG
410644	3-14-3	426	2313	2332	0	TCCGGCAGCAGATGGCAACG
							410645	3-14-3	427	2314	2333	0	CTCCGGCAGCAGATGGCAAC
410646	3-14-3	428	2315	2334	0	GCTCCGGCAGCAGATGGCAA

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:1 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 2-13-5 breach and widens motif in the table 1.Table 4 illustration the antisense compounds widened of the breach of target SEQ ID NO:1, it has the 2-13-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 4: the breach polymers antisense compounds of target SEQ ID NO:1 with 2-13-5 motif

ISIS number	Motif	SEQ ID NO	5 ' initiation site to SEQ ID NO:1	3 ' initiation site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410647	2-13-5	184	597	616	0	TGAGGTATCCCCGGCGGGCA
410648	2-13-5	185	598	617	0	GTGAGGTATCCCCGGCGGGC
							410649	2-13-5	186	599	618	0	GGTGAGGTATCCCCGGCGGG
410650	2-13-5	11	600	619	0	TGGTGAGGTATCCCCGGCGG
							410651	2-13-5	187	601	620	0	TTGGTGAGGTATCCCCGGCG
410652	2-13-5	188	602	621	0	CTTGGTGAGGTATCCCCGGC
							410653	2-13-5	189	603	622	0	TCTTGGTGAGGTATCCCCGG

Isis number	Motif	SEQ ID NO	5 ' initiation site to SEQ ID NO:1	3 ' initiation site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410654	2-13-5	190	604	623	0	ATCTTGGTGAGGTATCCCCG
410655	2-13-5	191	605	624	0	GATCTTGGTGAGGTATCCCC
							410656	2-13-5	12	606	625	0	GGATCTTGGTGAGGTATCCC
410657	2-13-5	192	607	626	0	AGGATCTTGGTGAGGTATCC
							410658	2-13-5	243	997	1016	0	GCCACGCCGGCATCCCGGCC
410659	2-13-5	244	998	1017	0	GGCCACGCCGGCATCCCGGC
							410660	2-13-5	245	999	1018	0	TGGCCACGCCGGCATCCCGG
410661	2-13-5	246	1000	1019	0	TTGGCCACGCCGGCATCCCG
							410662	2-13-5	247	1001	1020	0	CTTGGCCACGCCGGCATCCC
410663	2-13-5	248	1002	1021	0	CCTTGGCCACGCCGGCATCC
							410664	2-13-5	249	1003	1022	0	CCCTTGGCCACGCCGGCATC
410665	2-13-5	28	1004	1023	0	ACCCTTGGCCACGCCGGCAT
							410666	2-13-5	250	1005	1024	0	CACCCTTGGCCACGCCGGCA
410667	2-13-5	251	1006	1025	0	GCACCCTTGGCCACGCCGGC
							410668	2-13-5	252	1007	1026	0	GGCACCCTTGGCCACGCCGG
410669	2-13-5	253	1008	1027	0	TGGCACCCTTGGCCACGCCG
							410670	2-13-5	254	1009	1028	0	CTGGCACCCTTGGCCACGCC
410671	2-13-5	255	1010	1029	0	GCTGGCACCCTTGGCCACGC
							410672	2-13-5	348	1562	1581	0	AGGGAACCAGGCCTCATTGA
410673	2-13-5	349	1563	1582	0	CAGGGAACCAGGCCTCATTG
							410674	2-13-5	49	1564	1583	0	TCAGGGAACCAGGCCTCATT
410675	2-13-5	350	1565	1584	0	CTCAGGGAACCAGGCCTCAT
							410676	2-13-5	351	1566	1585	0	CCTCAGGGAACCAGGCCTCA
410677	2-13-5	352	1567	1586	0	TCCTCAGGGAACCAGGCCTC
							410678	2-13-5	353	1568	1587	0	GTCCTCAGGGAACCAGGCCT
410679	2-13-5	50	1569	1588	0	GGTCCTCAGGGAACCAGGCC
							410680	2-13-5	354	1570	1589	0	TGGTCCTCAGGGAACCAGGC
410681	2-13-5	355	1571	1590	0	CTGGTCCTCAGGGAACCAGG
							410682	2-13-5	356	1572	1591	0	GCTGGTCCTCAGGGAACCAG
410683	2-13-5	376	1849	1868	0	CACCTGGCAATGGCGTAGAC
							410684	2-13-5	377	1850	1869	0	GCACCTGGCAATGGCGTAGA
410685	2-13-5	378	1851	1870	0	AGCACCTGGCAATGGCGTAG
							410686	2-13-5	379	1852	1871	0	CAGCACCTGGCAATGGCGTA
410687	2-13-5	380	1853	1872	0	GCAGCACCTGGCAATGGCGT
							410688	2-13-5	381	1854	1873	0	GGCAGCACCTGGCAATGGCG
410689	2-13-5	382	1855	1874	0	AGGCAGCACCTGGCAATGGC
							410690	2-13-5	383	1856	1875	0	CAGGCAGCACCTGGCAATGG
410691	2-13-5	384	1857	1876	0	GCAGGCAGCACCTGGCAATG
							410692	2-13-5	58	1858	1877	0	AGCAGGCAGCACCTGGCAAT
410693	2-13-5	385	1859	1878	0	TAGCAGGCAGCACCTGGCAA
							410694	2-13-5	388	1915	1934	0	GTCCCCATGCTGGCCTCAGC
410695	2-13-5	389	1916	1935	0	GGTCCCCATGCTGGCCTCAG
							410696	2-13-5	390	1917	1936	0	GGGTCCCCATGCTGGCCTCA
410697	2-13-5	391	1918	1937	0	CGGGTCCCCATGCTGGCCTC
							410698	2-13-5	392	1919	1938	0	ACGGGTCCCCATGCTGGCCT
410699	2-13-5	59	1920	1939	0	CACGGGTCCCCATGCTGGCC
							410700	2-13-5	393	1921	1940	0	ACACGGGTCCCCATGCTGGC
410701	2-13-5	394	1922	1941	0	GACACGGGTCCCCATGCTGG
							410702	2-13-5	395	1923	1942	0	GGACACGGGTCCCCATGCTG

ISIS number	Motif	SEQ ID NO	5 ' initiation site to SEQ ID NO:1	3 ' initiation site to SEQ ID NO:1	Mispairing	Sequence (5 '-3 ')
							410703	2-13-5	396	1924	1943	0	TGGACACGGGTCCCCATGCT
410704	2-13-5	397	1925	1944	0	GTGGACACGGGTCCCCATGC
							410705	2-13-5	398	1926	1945	0	AGTGGACACGGGTCCCCATG
410706	2-13-5	399	1927	1946	0	CAGTGGACACGGGTCCCCAT
							410707	2-13-5	400	1928	1947	0	GCAGTGGACACGGGTCCCCA
410708	2-13-5	401	1929	1948	0	GGCAGTGGACACGGGTCCCC
							410709	2-13-5	402	1930	1949	0	TGGCAGTGGACACGGGTCCC
410710	2-13-5	403	1931	1950	0	GTGGCAGTGGACACGGGTCC
							410711	2-13-5	404	1932	1951	0	GGTGGCAGTGGACACGGGTC
410712	2-13-5	405	1933	1952	0	TGGTGGCAGTGGACACGGGT
							410713	2-13-5	60	2100	2119	0	CTTTGCATTCCAGACCTGGG
410714	2-13-5	411	2101	2120	0	ACTTTGCATTCCAGACCTGG
							410715	2-13-5	412	2102	2121	0	GACTTTGCATTCCAGACCTG
410716	2-13-5	413	2103	2122	0	TGACTTTGCATTCCAGACCT
							410717	2-13-5	414	2104	2123	0	TTGACTTTGCATTCCAGACC
410718	2-13-5	61	2105	2124	0	CTTGACTTTGCATTCCAGAC
							410719	2-13-5	419	2305	2324	0	CAGATGGCAACGGCTGTCAC
410720	2-13-5	420	2306	2325	0	GCAGATGGCAACGGCTGTCA
							410721	2-13-5	421	2307	2326	0	AGCAGATGGCAACGGCTGTC
410722	2-13-5	422	2308	2327	0	CAGCAGATGGCAACGGCTGT
							410723	2-13-5	423	2309	2328	0	GCAGCAGATGGCAACGGCTG
410724	2-13-5	62	2310	2329	0	GGCAGCAGATGGCAACGGCT
							410725	2-13-5	424	2311	2330	0	CGGCAGCAGATGGCAACGGC
410726	2-13-5	425	2312	2331	0	CCGGCAGCAGATGGCAACGG
							410727	2-13-5	426	2313	2332	0	TCCGGCAGCAGATGGCAACG
410728	2-13-5	427	2314	2333	0	CTCCGGCAGCAGATGGCAAC
							410729	2-13-5	428	2315	2334	0	GCTCCGGCAGCAGATGGCAA

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:1 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 3-13-4 breach and widens motif in the table 1.Table 5 illustration the antisense compounds widened of the breach of target SEQ ID NO:1, it has the 3-13-4 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 5: the breach polymers antisense compounds of target SEQ ID NO:1 with 3-13-4 motif

Oligomer	Motif	SEQ ID NO：	5 ' initiation site	3 ' initiation site	Mispairing	The oligomer sequence
							405526	3-13-4	236	963	982	0	CCAGGTGGGTGCCATGACTG
405557	3-13-4	50	1569	1588	0	GGTCCTCAGGGAACCAGGCC
							405564	3-13-4	373	1737	1756	0	AACTGGAGCAGCTCAGCAGC

Following embodiment has been listed the target region of PCSK9 nucleic acid.The example of also having showed the antisense compounds of these target regions of target.It is any to connecting or examine the modification of base between sugared module, nucleosides to should be appreciated that the sequence of listing among each SEQ ID NO is independent of.Therefore, can comprise independently connecting or examine one or more modifications of base between sugared module, nucleosides by the defined antisense compounds of SEQ ID NO.Represent to examine the combination of base sequence and motif by the antisense compounds of Isis numbering (Isis number) description.

In certain embodiments, a zone (range) of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, the following Nucleotide zone of the targeting compounds SEQ IDNO:1 of so shared at least one 8 Nucleotide core sequence:

294-317,406-440,406-526,410-436,410-499,446-526,545-581,591-619,591-704,591-743,595-622,600-626,600-639,600-670,601-628,602-628,603-630,611-636,620-647,638-665,648-674,657-684,705-743,782-810,821-859,835-859,835-917,835-942,860-887,860-899,860-909,860-917,869-895,878-905,888-909,923-952,960-1034,960-1173,960-986,967-991,970-1023,970-1064,970-1117,970-996,977-1004,985-1011,989-1016,992-1019,997-1024,997-1024,998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076-1096,1088-1115,1098-1123,1200-1251,1210-1237,1219-1245,1228-1251,1273-1444,1295-1316,1318-1345,1328-1354,1337-1361,1344-1371,1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526-1624,1532-1558,1541-1568,1552-1579,1560-1587,1561-1589,1564-1591,1565-1592,1566-1592,1567-1592,1570-1597,1571-1599,1605-1706,1628-1706,1640-1666,1672-1698,1681-1706,1735-1761,1735-1765,1740-1765,1849-1876,1849-1879,1850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854-1879,1905-1955,1915-1942,1916-1943,1917-1944,1918-1945,1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040-2126,2100-2126,2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227-3456,3472-3496 or 3543-3569.

In certain embodiments, target region is the Nucleotide 294-317 of SEQ ID NO:1.In certain embodiments, the Nucleotide 294-317 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:159 or 160.In some such embodiment, the antisense compounds of the Nucleotide 294-317 of target SEQ ID NO:1 is selected from ISIS NO:410742 or 405999.

In certain embodiments, target region is the Nucleotide 406-440 of SEQ ID NO:1.In certain embodiments, the Nucleotide 406-440 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:7,8,162,163,164,165,166,167,168,169 or 170 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 406-440 of target SEQ ID NO:1 is selected from ISIS NO:405861,405862,405863,405864,395152,399874,405865,405866,405867,405868,399793,399949 or 410743.

In certain embodiments, target region is the Nucleotide 406-526 of SEQ ID NO:1.In certain embodiments, the Nucleotide 406-526 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:7,8,9,162,163,164,165,166,167,168,169,170,171,172,173,174,175 or 176 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 406-526 of target SEQ ID NO:1 is selected from ISIS NO:405861,405862,405863,405864,395152,399874,405865,405866,405867,405868,399793,399950,410743,410744,410745,395153,399875,406000,406001,406002 or 410746.

In certain embodiments, target region is the Nucleotide 410-436 of SEQ ID NO:1.In certain embodiments, the Nucleotide 410-436 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:7,8,166,167,168,169 or 169 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 410-436 of target SEQ ID NO:1 is selected from ISIS NO:395152,399874,405865,405866,405867,405868 or 399793.

In certain embodiments, target region is the Nucleotide 410-499 of SEQ ID NO:1.In certain embodiments, the Nucleotide 410-499 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:7,8,9,166,167,169,170,171 or 172 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 410-499 of target SEQ IDNO:1 is selected from ISIS NO:395152,399874,405865,405866,405867,405868,399793,399949,410743,410744,410745,395153 or 399875.

In certain embodiments, target region is the Nucleotide 446-526 of SEQ ID NO:1.In certain embodiments, the Nucleotide 446-526 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:9,171,172,173,174,175 or 176 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 446-526 of target SEQ ID NO:1 is selected from ISIS NO:410744,410745,395153,399875,406000,406001,406002 or 410746.

In certain embodiments, target region is the Nucleotide 545-581 of SEQ ID NO:1.In certain embodiments, the Nucleotide 545-581 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:10,177,178,179,180 or 181 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 545-581 of target SEQ ID NO:1 is selected from ISIS NO:410747,406003,406004,406005,395154,399876 or 406006.

In certain embodiments, target region is the Nucleotide 591-619 of SEQ ID NO:1.In certain embodiments, the Nucleotide 591-619 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,182,183,184,185 or 186 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 591-619 of target SEQ ID NO:1 is selected from ISIS NO:410748,406007,410529,410574,410647,410530,410575,410648,410531,410576,410649,395155,399877 or 410650.

In certain embodiments, target region is the Nucleotide 591-704 of SEQ ID NO:1.In certain embodiments, the Nucleotide 591-704 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,13,14,15,16,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207 or 208 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 591-704 of target SEQ ID NO:1 is selected from ISIS NO:410748,406007,410529,410574,410647,410530,410575,410648,410531,410576,410649,395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656 or 410751.

In certain embodiments, target region is the Nucleotide 591-743 of SEQ ID NO:1.In certain embodiments, the Nucleotide 591-743 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,13,14,15,16,17,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208 or 209 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 591-743 of target SEQ ID NO:1 is selected from ISIS NO:410748,406007,410529,410574,410647,410530,410575,410648,410531,410576,410649,395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656 or 410752.

In certain embodiments, target region is the Nucleotide 595-622 of SEQ ID NO:1.In certain embodiments, the Nucleotide 595-622 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,183,184,185,186,187,188 or 189 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 595-622 of target SEQ IDNO:1 is selected from ISIS NO:406007,410529,410574,410647,410530,410575,410648,410531,410576,410649,395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579 or 410653.

In certain embodiments, target region is the Nucleotide 600-626 of SEQ ID NO:1.In certain embodiments, the Nucleotide 600-626 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,87,188,189,190,191 or 192 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 600-626 of target SEQ IDNO:1 is selected from ISIS NO:395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582 or 410657.

In certain embodiments, target region is the Nucleotide 600-639 of SEQ ID NO:1.In certain embodiments, the Nucleotide 600-639 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,13,14,187,188,189,190,191,192,193,194,195 or 196 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 600-639 of target SEQ ID NO:1 is selected from ISISNO:395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582,410657,406010,406011,406012,399795,399951,406013,395156 or 399878.

In certain embodiments, target region is the Nucleotide 600-670 of SEQ ID NO:1.In certain embodiments, the Nucleotide 600-670 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,13,14,15,16,187,188,189,190,191,192,193,194,195,196,197,198 or 199 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 600-670 of target SEQ ID NO:1 is selected from ISIS NO:395155,399877,410650,410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582,410657,406010,406011,406012,399795,399951,406013,395156,399878 or 399952.

In certain embodiments, target region is the Nucleotide 601-628 of SEQ ID NO:1.In certain embodiments, the Nucleotide 601-628 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,187,188,189,190,191,192 or 193 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 601-628 of target SEQ IDNO:1 is selected from ISIS NO:410532,410577,410651,406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582,410657 or 406010.

In certain embodiments, target region is the Nucleotide 602-628 of SEQ ID NO:1.In certain embodiments, the Nucleotide 602-628 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,188,189,190,191,192 or 193 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 602-628 of target SEQ ID NO:1 is selected from ISIS NO:406008,410578,410652,410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582,410657 or 406010.

In certain embodiments, target region is the Nucleotide 603-630 of SEQ ID NO:1.In certain embodiments, the Nucleotide 603-630 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,189,190,191,192,193 or 194 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 603-630 of target SEQ ID NO:1 is selected from ISIS NO:410533,410579,410653,406009,410580,410654,410534,410581,410655,399794,399950,410656,410535,410582,410657,406010 or 406011.

In certain embodiments, target region is the Nucleotide 611-636 of SEQ ID NO:1.In certain embodiments, the Nucleotide 611-636 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:13,194,195 or 196 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 611-636 of target SEQ ID NO:1 is selected from ISIS NO:406011,406012,399795,399951 or 406013.

In certain embodiments, target region is the Nucleotide 620-647 of SEQ ID NO:1.In certain embodiments, the Nucleotide 620-647 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:14 or 197.In some such embodiment, the antisense compounds of the Nucleotide 620-647 of target SEQ ID NO:1 is selected from ISIS NO:395156,399878 or 410749.

In certain embodiments, target region is the Nucleotide 638-665 of SEQ ID NO:1.In certain embodiments, the Nucleotide 638-665 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:15 or 198.In some such embodiment, the antisense compounds of the Nucleotide 638-665 of target SEQ ID NO:1 is selected from ISIS NO:410750,395157 or 399879.

In certain embodiments, target region is the Nucleotide 648-674 of SEQ ID NO:1.In certain embodiments, the Nucleotide 648-674 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:16,199,200 or 201 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 648-674 of target SEQ ID NO:1 is selected from ISIS NO:406014,399796,399952,406015 or 406016.

In certain embodiments, target region is the Nucleotide 657-684 of SEQ ID NO:1.In certain embodiments, the Nucleotide 657-684 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:202,203,204,205 or 206 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 657-684 of target SEQ ID NO:1 is selected from ISIS NO:410730,406017,406018,406019 or 406020.

In certain embodiments, target region is the Nucleotide 705-743 of SEQ ID NO:1.In certain embodiments, the Nucleotide 705-743 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:17 or 209.In some such embodiment, the antisense compounds of the Nucleotide 705-743 of target SEQ ID NO:1 is selected from ISIS NO:395158,399880 or 410752.

In certain embodiments, target region is the Nucleotide 782-810 of SEQ ID NO:1.In certain embodiments, the Nucleotide 782-810 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:18,210,211,212,213 or 214 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 782-810 of target SEQ ID NO:1 is selected from ISIS NO:406021,406022,395159,399881,406023,406024 or 410732.

In certain embodiments, target region is the Nucleotide 821-859 of SEQ ID NO:1.In certain embodiments, the Nucleotide 821-859 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,215,216 or 217 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 821-859 of target SEQ ID NO:1 is selected from ISIS NO:410753,406025,395160,399882,406026,399797 or 399953.

In certain embodiments, target region is the Nucleotide 835-859 of SEQ ID NO:1.In certain embodiments, the Nucleotide 835-859 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20 or 217 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 835-859 of target SEQ ID NO:1 is selected from ISIS NO:395160,399882,406026,399797 or 399953.

In certain embodiments, target region is the Nucleotide 835-917 of SEQ ID NO:1.In certain embodiments, the Nucleotide 835-917 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,21,22,23,24,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232 or 233 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 835-917 of target SEQ IDNO:1 is selected from ISIS NO:395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162,399884 or 410754.

In certain embodiments, target region is the Nucleotide 835-942 of SEQ ID NO:1.In certain embodiments, the Nucleotide 835-942 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,21,22,23,24,25,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232 or 233 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 835-942 of target SEQ ID NO:1 is selected from ISIS NO:395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162,399884,410754,395163 or 399885.

In certain embodiments, target region is the Nucleotide 860-887 of SEQ ID NO:1.In certain embodiments, the Nucleotide 860-887 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,218,219,220,221,222 or 223 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 860-887 of target SEQ IDNO:1 is selected from ISIS NO:395161,399883,405869,405870,405871,405872,399798,399954,405873 or 405874.

In certain embodiments, target region is the Nucleotide 860-899 of SEQ ID NO:1.In certain embodiments, the Nucleotide 860-899 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,218,219,220,221,222,223,224,225,226,227 or 228 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 860-899 of target SEQ ID NO:1 is selected from ISIS NO:395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799 or 399955.

In certain embodiments, target region is the Nucleotide 860-909 of SEQ ID NO:1.In certain embodiments, the Nucleotide 860-909 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,24,218,219,220,221,222,223,224,225,226,227,228,229,230,231 or 232 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 860-909 of target SEQ ID NO:1 is selected from ISIS NO:395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162 or 399884.

In certain embodiments, target region is the Nucleotide 860-917 of SEQ ID NO:1.In certain embodiments, the Nucleotide 860-917 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,24,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232 or 233 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 860-917 of target SEQ ID NO:1 is selected from ISIS NO:395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162,399884 or 410754.

In certain embodiments, target region is the Nucleotide 869-895 of SEQ ID NO:1.In certain embodiments, the Nucleotide 869-895 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:224,225,226 or 227 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 869-895 of target SEQ ID NO:1 is selected from ISIS NO:405875,405876,406027 or 406028.

In certain embodiments, target region is the Nucleotide 878-905 of SEQ ID NO:1.In certain embodiments, the Nucleotide 878-905 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:23,228,229,230 or 231 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 878-905 of target SEQ ID NO:1 is selected from ISIS NO:406029,399799,399955,406030,406031 or 410733.

In certain embodiments, target region is the Nucleotide 888-909 of SEQ ID NO:1.In certain embodiments, the Nucleotide 888-909 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:24 or 232.In some such embodiment, the antisense compounds of the Nucleotide 888-909 of target SEQ ID NO:1 is selected from ISIS NO:406032,395162 or 399884.

In certain embodiments, target region is the Nucleotide 923-952 of SEQ ID NO:1.In certain embodiments, the Nucleotide 923-952 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:25 or 234.In some such embodiment, the antisense compounds of the Nucleotide 923-952 of target SEQ ID NO:1 is selected from ISIS NO:395163,399885 or 410755.

In certain embodiments, target region is the Nucleotide 960-1034 of SEQ ID NO:1.In certain embodiments, the Nucleotide 960-1034 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255 or 256 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 960-1034 of target SEQ ID NO:1 is selected from ISISNO:410756,405526,405604,406033,395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880 or 410758.

In certain embodiments, target region is the Nucleotide 960-1173 of SEQ ID NO:1.In certain embodiments, the Nucleotide 960-1173 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272 or 273 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 960-1173 of target SEQ ID NO:1 is selected from ISIS NO:410756,405526,405604,406033,395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880 or 410763.

In certain embodiments, target region is the Nucleotide 960-986 of SEQ ID NO:1.In certain embodiments, the Nucleotide 960-986 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:235,236 or 237 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 960-986 of target SEQ ID NO:1 is selected from ISIS NO:410756,405526,405604 or 406033.

In certain embodiments, target region is the Nucleotide 967-991 of SEQ ID NO:1.In certain embodiments, the Nucleotide 967-991 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:237 or 238.In some such embodiment, the antisense compounds of the Nucleotide 967-991 of target SEQ ID NO:1 is selected from ISIS NO:406033 or 406034.

In certain embodiments, target region is the Nucleotide 970-1023 of SEQ ID NO:1.In certain embodiments, the Nucleotide 970-1023 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,238,239,240,241,242,243,244,245,246,247,248 or 249 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 970-1023 of target SEQ ID NO:1 is selected from ISIS NO:395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887 or 410665.

In certain embodiments, target region is the Nucleotide 970-1064 of SEQ ID NO:1.In certain embodiments, the Nucleotide 970-1064 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,29,30,238,239,240,241,242,243,244,245,246,247,248,149,250,251,252,253,254,255,256,257,258,259,260,261,262 or 263 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 970-1064 of target SEQ ID NO:1 is selected from ISIS NO:395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887 or 399957.

In certain embodiments, target region is the Nucleotide 970-1117 of SEQ ID NO:1.In certain embodiments, the Nucleotide 970-1117 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,29,30,31,32,238,239,240,241,242,243,244,245,246,247,248,149,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265 or 266 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 970-1117 of target SEQ ID NO:1 is selected from ISIS NO:395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887 or 399890.

In certain embodiments, target region is the Nucleotide 970-996 of SEQ ID NO:1.In certain embodiments, the Nucleotide 970-996 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27 or 238 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 970-996 of target SEQ ID NO:1 is selected from ISIS NO:395164,399886,406034,399800,399956 or 406035.

In certain embodiments, target region is the Nucleotide 977-1004 of SEQ ID NO:1.In certain embodiments, the Nucleotide 977-1004 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:239 or 240.In some such embodiment, the antisense compounds of the Nucleotide 977-1004 of target SEQ ID NO:1 is selected from ISIS NO:406035 or 410757.

In certain embodiments, target region is the Nucleotide 985-1011 of SEQ ID NO:1.In certain embodiments, the Nucleotide 985-1011 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:240,241 or 242 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 985-1011 of target SEQ ID NO:1 is selected from ISIS NO:410757,406036 or 406037.

In certain embodiments, target region is the Nucleotide 989-1016 of SEQ ID NO:1.In certain embodiments, the Nucleotide 989-1016 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:241,242 or 243 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 989-1016 of target SEQ ID NO:1 is selected from ISIS NO:406036,406037,410536,410583 or 410658.

In certain embodiments, target region is the Nucleotide 992-1019 of SEQ ID NO:1.In certain embodiments, the Nucleotide 992-1019 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:242,243,244,245 or 246 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 992-1019 of target SEQ ID NO:1 is selected from ISIS NO:406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586 or 410661.

In certain embodiments, target region is the Nucleotide 997-1024 of SEQ ID NO:1.In certain embodiments, the Nucleotide 997-1024 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:243,244,245,246,247,248,249 or 250 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 997-1024 of target SEQ ID NO:1 is selected from ISIS NO:410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,409126,410665,405881,410590 or 410666.

In certain embodiments, target region is the Nucleotide 997-1024 of SEQ ID NO:1.In certain embodiments, the Nucleotide 997-1024 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:243,244,245,246,247,248,249 or 250 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 997-1024 of target SEQ ID NO:1 is selected from ISIS NO:410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,409126,410665,405881,410590 or 410666.

In certain embodiments, target region is the Nucleotide 998-1025 of SEQ ID NO:1.In certain embodiments, the Nucleotide 998-1025 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,244,245,246,247,248,249,250 or 251 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 998-1025 of target SEQ ID NO:1 is selected from ISIS NO:410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591 or 410667.

In certain embodiments, target region is the Nucleotide 999-1026 of SEQ ID NO:1.In certain embodiments, the Nucleotide 999-1026 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,245,246,247,248,249,250,251 or 252 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 999-1026 of target SEQ ID NO:1 is selected from ISIS NO:406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405833,410592 or 410668.

In certain embodiments, target region is the Nucleotide 1000-1027 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1000-1027 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,246,247,248,249,250,251,252 or 253 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1000-1027 of target SEQ ID NO:1 is selected from ISIS NO:405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405833,410592,410668,405884,410593 or 410669.

In certain embodiments, target region is the Nucleotide 1001-1028 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1001-1028 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,247,248,249,250,251,252,253 or 254 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1001-1028 of target SEQ ID NO:1 is selected from ISIS NO:405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405833,410592,410668,405884,410593,410669,410538,410594 or 410670.

In certain embodiments, target region is the Nucleotide 1002-1029 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1002-1029 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,248,249,250,251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1002-1029 of target SEQ ID NO:1 is selected from ISIS NO:405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405833,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1003-1029 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1003-1029 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,249,250,251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1003-1029 of target SEQ ID NO:1 is selected from ISIS NO:405880,410589,410664,395165,399887,409126,410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1004-1029 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1004-1029 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,250,251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1004-1029 of target SEQ IDNO:1 is selected from ISIS NO:395165,399887,409126,410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1005-1029 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1005-1029 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:250,251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1005-1029 of target SEQ ID NO:1 is selected from ISIS NO:410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1006-1029 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1006-1029 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1006-1029 of target SEQ ID NO:1 is selected from ISIS NO:405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1007-1034 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1007-1034 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:252,253,254,255 or 256 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1007-1034 of target SEQ ID NO:1 is selected from ISIS NO:405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595,410671 or 410758.

In certain embodiments, target region is the Nucleotide 1036-1061 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1036-1061 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:29,257,258 or 259 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1036-1061 of target SEQ ID NO:1 is selected from ISIS NO:406039,406040,395166,399888 or 406041.

In certain embodiments, target region is the Nucleotide 1045-1072 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1045-1072 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:30,260,261 or 262 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1045-1072 of target SEQ ID NO:1 is selected from ISIS NO:399801,399957,406042,406043 or 406044.

In certain embodiments, target region is the Nucleotide 1076-1096 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1076-1096 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:31 or 264.In some such embodiment, the antisense compounds of the Nucleotide 1076-1096 of target SEQ ID NO:1 is selected from ISIS NO:408642,395167 or 399889.

In certain embodiments, target region is the Nucleotide 1088-1115 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1088-1115 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:265 or 266.In some such embodiment, the antisense compounds of the Nucleotide 1088-1115 of target SEQ ID NO:1 is selected from ISIS NO:410760 or 406045.

In certain embodiments, target region is the Nucleotide 1098-1123 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1098-1123 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:32,267,268 or 269 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1098-1123 of target SEQ ID NO:1 is selected from ISIS NO:395168,399890,405909,405910 or 405911.

In certain embodiments, target region is the Nucleotide 1200-1251 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1200-1251 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,274,275,276,277,278,279,280,281,282,283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1200-1251 of target SEQ ID NO:1 is selected from ISIS NO:410764,395169,399891,405913,405914,405915,405916,410734,405917,405918,405919,405920,405921 or 405922.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1210-1237 in certain embodiments, the Nucleotide 1210-1237 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,275,276,277 or 278 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1210-1237 of target SEQ ID NO:1 is selected from ISIS NO:395169,399891,405913,405914,405915 or 405916.

In certain embodiments, target region is the Nucleotide 1219-1245 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1219-1245SEQ ID NO:1. of antisense compounds target SEQ ID NO:1 in certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:279,280,281 or 282 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1219-1245 of target SEQ ID NO:1 is selected from ISIS NO:410734,405917,405918 or 405919.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1228-1251of SEQID NO:1 in certain embodiments, the Nucleotide 1228-1251 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQID NO:283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1228-1251 of target SEQ IDNO:1 is selected from ISIS NO:405920,405921 or 405922.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1273-1444 in certain embodiments, the Nucleotide 1273-1444 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:34,35,36,37,38,39,40,41,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,316 or 318 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1273-1444 of target SEQ ID NO:1 is selected from ISIS NO:410765,410766,405923,395170,399892,410767,405924,410735,405925,405926,395171,399893,405927,395172,399894,405928,399802,399958,405929,395173,399895,405930,405931,405932,405933,405934,399803,399959,405935,410736,405936,395174 or 410769.

In certain embodiments, target region is the Nucleotide 1295-1316 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1295-1316 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:149 or 288.In some such embodiment, the antisense compounds of the Nucleotide 1295-1316 of target SEQ ID NO:1 is selected from ISIS NO:405923,395170 or 399892.

In certain embodiments, target region is the Nucleotide 1318-1345 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1318-1345 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:34,290,291,292 or 293 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1318-1345 of target SEQ ID NO:1 is selected from ISIS NO:405924,410735,405925,405926,395171 or 399893.

In certain embodiments, target region is the Nucleotide 1328-1354 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1328-1354 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:35,128,294 or 295 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1328-1354 of target SEQ ID NO:1 is selected from ISIS NO:405927,395172,399894,405928,399802 or 399958.

In certain embodiments, target region is the Nucleotide 1337-1361 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1337-1361 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:36,296 or 297 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1337-1361 of target SEQ ID NO:1 is selected from ISIS NO:405929,395173,399895 or 405930.

In certain embodiments, target region is the Nucleotide 1344-1371 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1344-1371 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:37,298,299,300 or 301 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1344-1371 of target SEQ ID NO:1 is selected from ISIS NO:405931,405932,405933,405934,399803 or 399959.

In certain embodiments, target region is the Nucleotide 1354-1377 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1354-1377 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:302,303 or 304 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1354-1377 of target SEQ ID NO:1 is selected from ISIS NO:405935,410736 or 405936.

In certain embodiments, target region is the Nucleotide 1380-1406 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1380-1406 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:305 or 306.In some such embodiment, the antisense compounds of the Nucleotide 1380-1406 of target SEQ ID NO:1 is selected from ISIS NO:410768 or 405937.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1389-1416 in certain embodiments, the Nucleotide 1389-1416 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:39,307,308,309 or 310 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1389-1416 of target SEQ ID NO:1 is selected from ISIS NO:395175,399897,405938,405939,405940 or 405941.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1400-1426 in certain embodiments, the Nucleotide 1400-1426 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:40,311,312,313 or 314 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1400-1426 of target SEQ ID NO:1 is selected from ISIS NO:399804,399960,405942,405943,410737 or 405944.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1409-1434 in certain embodiments, the Nucleotide 1409-1434 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:41,315,316 or 317 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1409-1434 of target SEQ ID NO:1 is selected from ISIS NO:405945,399805,399961,405946 or 405947.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1465-1491 in certain embodiments, the Nucleotide 1465-1491 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:42,101,319 or 320 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1465-1491 of target SEQ ID NO:1 is selected from ISIS NO:395176,399898,405948,399806,399962 or 405949.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1465-1602 in certain embodiments, the Nucleotide 1465-1602 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:42,43,44,45,46,47,48,49,50,51,87,101,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1465-1602 of target SEQ ID NO:1 is selected from ISISNO:395176,399898,405948,399806,399962,405949,405950,405951,399807,399963,405952,410738,405953,405954,410770,405955,405956,405957,405958,405959,405960,405961,399808,399964,405962,410739,405963,395177,399899,405964,399809,399965 or 399969.

In certain embodiments, target region is the Nucleotide 1474-1499 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1474-1499 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,321,322 or 323 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1474-1499 of target SEQ ID NO:1 is selected from ISIS NO:405950,405951,399807,399963 or 405952.

In certain embodiments, target region is the Nucleotide 1482-1519 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1482-1519 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:324,325,326 or 327 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1482-1519 of target SEQ ID NO:1 is selected from ISIS NO:410738,405953,405954 or 410770.

In certain embodiments, target region is the Nucleotide 1513-1540 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1513-1540 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:328,329,330,331 or 332 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1513-1540 of target SEQ ID NO:1 is selected from ISIS NO:405955,405956,405957,405958 or 405959.

In certain embodiments, target region is the Nucleotide 1523-1549 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1523-1549 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,333,334,335 or 336 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1523-1549 of target SEQ ID NO:1 is selected from ISIS NO:405960,405961,399808,399964,405962 or 410739.

In certain embodiments, target region is the Nucleotide 1526-1602 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1526-1602 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,45,46,47,48,49,50,51,87,335,336,337,338,339,340,341,342,343,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1526-1602 of target SEQ ID NO:1 is selected from ISIS NO:399808,399964,405962,410739,405963,395177,399899,405964,399809,399965,405965,405966,399810,399966,405967,405968,399811,399967,405969,405970,410740,405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674 or 399969.

In certain embodiments, target region is the Nucleotide 1526-1624 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1526-1624 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,45,46,47,48,49,50,51,87,119,335,336,337,338,339,340,341,342,343,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1526-1624 of target SEQ ID NO:1 is selected from ISIS NO:399808,399964,405962,410739,405963,395177,399899,405964,399809,399965,405965,405966,399810,399966,405967,405968,399811,399967,405969,405970,410740,405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674 or 399902.

In certain embodiments, target region is the Nucleotide 1532-1558 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1532-1558 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:45,46,337 or 338 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1532-1558 of target SEQ ID NO:1 is selected from ISIS NO:405963,395177,399899,405964,399809 or 399965.

In certain embodiments, target region is the Nucleotide 1541-1568 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1541-1568 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:47,340,341 or 342 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1541-1568 of target SEQ ID NO:1 is selected from ISIS NO:405965,405966,399810,399966,405967 or 405968.

In certain embodiments, target region is the Nucleotide 1552-1579 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1552-1579 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:48,343,344,345 or 346 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1552-1579 of target SEQ ID NO:1 is selected from ISIS NO:399811,399967,405969,405970,410740 or 405885.

In certain embodiments, target region is the Nucleotide 1560-1587 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1560-1587 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,346,347,348,349,350,351,352 or 353 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1560-1587 of target SEQ ID NO:1 is selected from ISIS NO:405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601 or 410678.

In certain embodiments, target region is the Nucleotide 1561-1589 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1561-1589 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,346,347,348,349,350,351,352,353 or 354 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1561-1589 of target SEQ ID NO:1 is selected from ISISNO:405886,405887,410596,410672,405888,410597,410673,399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,405557,410679,408653,410602 or 410680.

In certain embodiments, target region is the Nucleotide 1564-1591 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1564-1591 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,350,351,352,353,354,355 or 356 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1564-1591 of target SEQ ID NO:1 is selected from ISIS NO:399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,405557,410679,408653,410602,410680,405971,410603,410681,410540,410604 or 410682.

In certain embodiments, target region is the Nucleotide 1565-1592 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1565-1592 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,350,351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1565-1592 of target SEQ ID NO:1 is selected from ISIS NO:405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,405557,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region is the Nucleotide 1566-1592 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1566-1592 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1566-1592 of target SEQ ID NO:1 is selected from ISIS NO:405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,405557,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region be SEQ ID NO:1 Nucleotide 1567-1592 in certain embodiments, the Nucleotide 1567-1592 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1567-1592 of target SEQ ID NO:1 is selected from ISIS NO:405891,410600,410677,405892,410601,410678,395178,399900,405557,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region is the Nucleotide 1570-1597 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1570-1597 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:354,355,356,357 or 358 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1570-1597 of target SEQ ID NO:1 is selected from ISIS NO:408653,410602,410680,405971,410603,410681,410540,410604,410682,405972 or 405973.

In certain embodiments, target region is the Nucleotide 1571-1599 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1571-1599 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:87,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1571-1599 of target SEQ ID NO:1 is selected from ISIS NO:405971,410603,410681,410540,410604,410682,405972,395179,399901,405973 or 405974.

In certain embodiments, target region is the Nucleotide 1605-1706 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1605-1706 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,54,119,360,361,362,363,364,365,366,367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1605-1706 of target SEQ ID NO:1 is selected from ISIS NO:395180,399902,410771,395181,399903,405975,399814,399970,405976,405977,410772,405978,395182,399904,405979,405980,405981,410741,405982 or 405983.

In certain embodiments, target region is the Nucleotide 1628-1706 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1628-1706 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,54,360,361,362,363,364,365,366,367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1628-1706 of target SEQ ID NO:1 is selected from ISIS NO:410771,395181,399903,405975,399814,399970,405976,405977,410772,405978,395182,399904,405979,405980,405981,410741,405982 or 405983.

In certain embodiments, target region is the Nucleotide 1640-1666 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1640-1666 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,361 or 362 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1640-1666 of target SEQ ID NO:1 is selected from ISIS NO:395181,399903,405975,399814,399970 or 405976.

In certain embodiments, target region is the Nucleotide 1672-1698 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1672-1698 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:54,365,366 or 367 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1672-1698 of target SEQ ID NO:1 is selected from ISIS NO:405978,395182,399904,405979 or 405980.

In certain embodiments, target region is the Nucleotide 1681-1706 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1681-1706 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1681-1706 of target SEQ ID NO:1 is selected from ISIS NO:405981,410741,405982 or 405983.

In certain embodiments, target region is the Nucleotide 1735-1761 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1735-1761 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,372,373 or 374 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1735-1761 of target SEQ ID NO:1 is selected from ISIS NO:405984,405564,405641,405985,399815,399971 or 405986.

In certain embodiments, target region is the Nucleotide 1735-1765 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1735-1765 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,56,372,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1735-1765 of target SEQ ID NO:1 is selected from ISIS NO:405984,405564,405641,405985,399815,399971,405986,405987,399816 or 399972.

In certain embodiments, target region is the Nucleotide 1740-1765 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1740-1765 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,56,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1740-1765 of target SEQ ID NO:1 is selected from ISIS NO:399815,399971,405986,405987,399816 or 399972.

In certain embodiments, target region is the Nucleotide 1849-1876 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1849-1876 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:376,377,378,379,380,381,382,383 or 384 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1849-1876 of target SEQ ID NO:1 is selected from ISIS NO:410541,410605,410683,410542,410606,410684,410543,410607,410685,410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613 or 410691.

In certain embodiments, target region is the Nucleotide 1849-1879 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1849-1879 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,376,377,378,379,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1849-1879 of target SEQ ID NO:1 is selected from ISIS NO:410541,410605,410683,410542,410606,410684,410543,410607,410685,410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906,410692,410548,410614 or 405990.

In certain embodiments, target region is the Nucleotide 1850-1877 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1850-1877 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,377,378,379,380,381,382,383 or 384 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1850-1877 of target SEQ ID NO:1 is selected from ISIS NO:410542,410606,410684,410543,410607,410685,410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906 or 410692.

In certain embodiments, target region is the Nucleotide 1851-1877 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1851-1877 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,378,379,380,381,382,383 or 384 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1851-1877 of target SEQ ID NO:1 is selected from ISIS NO:410543,410607,410685,410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906 or 410692.

In certain embodiments, target region is the Nucleotide 1852-1878 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1852-1878 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,379,380,381,382,383,384 or 385 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1852-1878 of target SEQ ID NO:1 is selected from ISIS NO:410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906,410692,410548,410614 or 410693.

In certain embodiments, target region is the Nucleotide 1852-1879 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1852-1879 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,379,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1852-1879 of target SEQ ID NO:1 is selected from ISIS NO:410544,410608,410686,410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906,410692,410548,410614,410693 or 405990.

In certain embodiments, target region is the Nucleotide 1853-1879 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1853-1879 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1853-1879 of target SEQ ID NO:1 is selected from ISIS NO:410545,410609,410687,405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906,410692,410548,410614,410693 or 405990.

In certain embodiments, target region is the Nucleotide 1854-1879 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1854-1879 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1854-1879 of target SEQ IDNO:1 is selected from ISIS NO:405988,410610,410688,410546,410611,410689,405989,410612,410690,410547,410613,395184,410691,399906,410692,410548,410614,410693 or 405990.

In certain embodiments, target region is the Nucleotide 1905-1955 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1905-1955 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405 or 406 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1905-1955 of target SEQ ID NO:1 is selected from ISIS NO:410773,410549,410615,410694,410550,410616,410695,410551,410617,410696,410552,410618,410697,410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556 or 410774.

In certain embodiments, target region is the Nucleotide 1915-1942 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1915-1942 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,388,389,390,391,392,393,394 or 395 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1915-1942 of target SEQ ID NO:1 is selected from ISIS NO:410549,410615,410694,410550,410616,410695,410551,410617,410696,410552,410618,410697,410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622 or 410702.

In certain embodiments, target region is the Nucleotide 1916-1943 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1916-1943 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,389,390,391,392,393,394,395 or 396 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1916-1943 of target SEQ ID NO:1 is selected from ISIS NO:410550,410616,410695,410551,410617,410696,410552,410618,410697,410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623 or 410703.

In certain embodiments, target region is the Nucleotide 1917-1944 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1917-1944 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,390,391,392,393,394,395,396 or 397 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1917-1944 of target SEQ ID NO:1 is selected from ISIS NO:410551,410617,410696,410552,410618,410697,410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624 or 410704.

In certain embodiments, target region is the Nucleotide 1918-1945 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1918-1945 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,391,392,393,394,395,396,397 or 398 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1918-1945 of target SEQ ID NO:1 is selected from ISIS NO:410552,410618,410697,410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625 or 410705.

In certain embodiments, target region is the Nucleotide 1919-1946 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1919-1946 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,392,393,394,395,396,397 or 399 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1919-1946 of target SEQ ID NO:1 is selected from ISIS NO:410553,410619,410698,395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626 or 410706.

In certain embodiments, target region is the Nucleotide 1920-1939 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1920-1939 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:59.In some such embodiment, the antisense compounds of the Nucleotide 1920-1939 of target SEQ ID NO:1 is selected from ISIS NO:395185,399907 or 410699.

In certain embodiments, target region is the Nucleotide 1920-1947 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1920-1947 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,393,394,395,396,397,398,399 or 400 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1920-1947 of target SEQ ID NO:1 is selected from ISIS NO:395185,399907,410699,410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626,410706,405944,410627 or 410707.

In certain embodiments, target region is the Nucleotide 1921-1948 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1921-1948 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:393,394,395,396,397,398,399,400 or 401 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1921-1948 of target SEQ ID NO:1 is selected from ISIS NO:410554,410620,410700,405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626,410706,405944,410627,410707,410558,410628 or 410708.

In certain embodiments, target region is the Nucleotide 1922-1949 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1922-1949 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:394,395,396,397,398,399,400,401 or 402 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1922-1949 of target SEQ ID NO:1 is selected from ISIS NO:405991,410621,410701,410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626,410706,405944,410627,410707,410558,410628,410708,405995,410629 or 410709.

In certain embodiments, target region is the Nucleotide 1923-1950 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1923-1950 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:395,396,397,398,399,400,401,402 or 403 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1923-1950 of target SEQ ID NO:1 is selected from ISIS NO:410555,410622,410702,405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626,410706,405944,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630 or 410710.

In certain embodiments, target region is the Nucleotide 1924-1951 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1924-1951 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:396,397,398,399,400,401,402,403 or 404 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1924-1951 of target SEQ ID NO:1 is selected from ISIS NO:405992,410623,410703,410556,410624,410704,405993,410625,410705,410557,410626,410706,405994,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630,410710,410560,410631 or 410711.

In certain embodiments, target region is the Nucleotide 1925-1952 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1925-1952 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:397,398,399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1925-1952 of target SEQ ID NO:1 is selected from ISIS NO:410556,410624,410704,405993,410625,410705,410557,410626,410706,405994,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630,410710,410560,410631,410711,410561,410632 or 410712.

In certain embodiments, target region is the Nucleotide 1926-1952 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1926-1952 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:398,399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1926-1952 of target SEQ ID NO:1 is selected from ISIS NO:405993,410625,410705,410557,410626,410706,405994,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630,410710,410560,410631,410711,410561,410632 or 410712.

In certain embodiments, target region is the Nucleotide 1927-1952 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1927-1952 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1927-1952 of target SEQ IDNO:1 is selected from ISIS NO:410557,410626,410706,405994,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630,410710,410560,410631,410711,410561,410632 or 410712.

In certain embodiments, target region is the Nucleotide 1928-1955 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1928-1955 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:400,401,402,403,404,405 or 406 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1928-1955 of target SEQ IDNO:1 is selected from ISIS NO:405994,410627,410707,410558,410628,410708,405995,410629,410709,410559,410630,410710,410560,410631,410711,410561,410632,410712 or 410774.

In certain embodiments, target region is the Nucleotide 1962-2059 of SEQ ID NO:1.In certain embodiments, the Nucleotide 1962-2059 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:407,408,409 or 410 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1962-2059 of target SEQ ID NO:1 is selected from ISIS NO:410775,410776,410777 or 410778.

In certain embodiments, target region is the Nucleotide 2040-2126 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2040-2126 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,410,411,412,413,414 or 415.In some such embodiment, the antisense compounds of targeted nucleotide 2040-2126 is selected from ISIS NO:410778,395186,399908,410713,410562,410633,410714,405996,410634,410715,410563,410635,410716,410564,410636,410717,399817,399973,410718 or 405997.

In certain embodiments, target region is the Nucleotide 2100-2126 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2100-2126 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414 or 415 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2100-2126 of target SEQ IDNO:1 is selected from ISIS NO:395186,399908,410713,410562,410633,410714,405996,410634,410715,410563,410635,410716,410564,410636,410717,399817,399973,410718 or 405997.

In certain embodiments, target region is the Nucleotide 2100-2139 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2100-2139 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414,415 or 416 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2100-2139 of target SEQ ID NO:1 is selected from ISIS NO:395186,399908,410713,410562,410633,410714,405996,410634,410715,410563,410635,410716,410564,410636,410717,399817,399973,410718,405997 or 410779.

In certain embodiments, target region is the Nucleotide 2100-2206 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2100-2206 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414,415,416,417 or 418 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2100-2206 of target SEQ ID NO:1 is selected from ISISNO:395186,399908,410713,410562,410633,410714,405996,410634,410715,410563,410635,410716,410564,410636,410717,399817,399973,410718,405997,405997,410780 or 410781.

In certain embodiments, target region is the Nucleotide 2101-2126 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2101-2126 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:61,411,412,413,414 or 415 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2101-2126 of target SEQ ID NO:1 is selected from ISIS NO:410562,410633,410714,405996,410634,410715,410563,410635,410716,410564,410636,410717,399817,399973,410718 or 405997.

In certain embodiments, target region is the Nucleotide 2305-2332 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2305-2332 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425 or 426 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2305-2332 of target SEQ ID NO:1 is selected from ISIS NO:410565,410637,410719,410566,410638,410720,410567,410639,410721,410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644 or 410727.

In certain embodiments, target region is the Nucleotide 2305-2354 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2305-2354 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425,426,427,428,429 or 430 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2305-2354 of target SEQ ID NO:1 is selected from ISIS NO:410565,410637,410719,410566,410638,410720,410567,410639,410721,410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645,410728,410573,410646 or 410783.

In certain embodiments, target region is the Nucleotide 2306-2333 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2306-2333 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,420,421,422,423,424,425,426 or 427 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2306-2333 of target SEQ ID NO:1 is selected from ISIS NO:410566,410638,410720,410567,410639,410721,410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645 or 410728.

In certain embodiments, target region is the Nucleotide 2307-2334 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2307-2334 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,421,422,423,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2307-2334 of target SEQ ID NO:1 is selected from ISIS NO:410567,410639,410721,410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2308-2334 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2308-2334 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,422,423,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2308-2334 of target SEQ ID NO:1 is selected from ISIS NO:410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2309-2334 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2309-2334 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,423,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2309-2334 of target SEQ IDNO:1 is selected from ISIS NO:410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2310-2334 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2310-2334 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2310-2334 of target SEQ ID NO:1 is selected from ISIS NO:395187,399909,410724,410570,410642,410725,410571,410643,410726,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2410-2434 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2410-2434 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:63 or 154.In some such embodiment, the antisense compounds of the Nucleotide 2410-2434 of target SEQ ID NO:1 is selected from ISIS NO:395188,399910,399818 or 399974.

In certain embodiments, target region is the Nucleotide 2504-2528 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2504-2528 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:64 or 65.In some such embodiment, the antisense compounds of the Nucleotide 2504-2528 of target SEQ ID NO:1 is selected from ISIS NO:395189,399911,399819 or 399975.

In certain embodiments, target region is the Nucleotide 2509-2528 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2509-2528 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:65.In some such embodiment, the antisense compounds of the Nucleotide 2509-2528 of target SEQ ID NO:1 is selected from ISIS NO:399819 or 399975.

In certain embodiments, target region is the Nucleotide 2582-2625 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2582-2625 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:66,67 or 122 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2582-2625 of target SEQ ID NO:1 is selected from ISIS NO:399820,399976,395190,399912,395191 or 399913.

In certain embodiments, target region is the Nucleotide 2606-2668 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2606-2668 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:67 or 153.In some such embodiment, the antisense compounds of the Nucleotide 2606-2668 of target SEQ ID NO:1 is selected from ISIS NO:395191,399913,395192 or 399914.

In certain embodiments, target region is the Nucleotide 2828-2855 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2828-2855 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:69,431,432,433,434,435,436,437 or 438 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2828-2855 of target SEQ ID NO:1 is selected from ISIS NO:405893,405894,405895,405896,395194,399916,405897,405898,405899 or 405900.

In certain embodiments, target region is the Nucleotide 2832-2851 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2832-2851 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:69.In some such embodiment, the antisense compounds of the Nucleotide 2832-2851 of target SEQ ID NO:1 is selected from ISIS NO:395194 or 399916.

In certain embodiments, target region is the Nucleotide 2900-2927 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2900-2927 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:70,71,439,440,441,442,443 or 444 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2900-2927 of target SEQ ID NO:1 is selected from ISIS NO:395195,399917,405901,405902,405903,405904,399821,399977,405905 or 405906.

In certain embodiments, target region is the Nucleotide 2900-2929 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2900-2929 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:70,71,439,440,441,442,443,444,446 or 446 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2900-2929 of target SEQ ID NO:1 is selected from ISISNO:395195,399917,405901,405902,405903,405904,399821,399977,405905,405906,405907 or 405908.

In certain embodiments, target region is the Nucleotide 2902-2927 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2902-2927 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:71,439,440,441,442,443 or 444 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2902-2927 of target SEQ IDNO:1 is selected from ISIS NO:405901,405902,405903,405904,399821,399977,405905 or 405906.

In certain embodiments, target region is the Nucleotide 2983-3007 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2983-3007 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:72 or 73.In some such embodiment, the antisense compounds of the Nucleotide 2983-3007 of target SEQ ID NO:1 is selected from ISIS NO:395196,399918,399822 or 399978.

In certain embodiments, target region is the Nucleotide 2983-3013 of SEQ ID NO:1.In certain embodiments, the Nucleotide 2983-3013 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:72,73 or 135 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2983-3013 of target SEQ ID NO:1 is selected from ISIS NO:395196,399918,399822,399978,399823 or 399979.

In certain embodiments, target region is the Nucleotide 3227-3252 of SEQ ID NO:1.In certain embodiments, the Nucleotide 3227-3252 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:74 or 112.In some such embodiment, the antisense compounds of the Nucleotide 3227-3252 of target SEQ ID NO:1 is selected from ISIS NO:395197,399919,399824 or 399980.

In certain embodiments, target region is the Nucleotide 3227-3456 of SEQ ID NO:1.In certain embodiments, the Nucleotide 3227-3456 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:74,75 or 112 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3227-3456 of target SEQ ID NO:1 is selected from ISIS NO:395197,399919,399824,399980,395198 or 399920.

In certain embodiments, target region is the Nucleotide 3472-3496 of SEQ ID NO:1.In certain embodiments, the Nucleotide 3472-3496 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:76 or 77.In some such embodiment, the antisense compounds of the Nucleotide 3472-3496 of target SEQ ID NO:1 is selected from ISIS NO:395199,399921,399825 or 399981.

In certain embodiments, target region is the Nucleotide 3543-3569 of SEQ ID NO:1.In certain embodiments, the Nucleotide 3543-3569 of antisense compounds target SEQ ID NO:1.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:78 or 99.In some such embodiment, the antisense compounds of the Nucleotide 3543-3569 of target SEQ ID NO:1 is selected from ISIS NO:395200,399922,399826 or 399982.

In certain embodiments, the antisense compounds target has

Accession number NT_032977.8 is (early than being stored on February 26th, 2006 And as SEQ IDNO:2 income this paper) the PCSK9 nucleic acid of sequence of Nucleotide 25475000-25504000.In some such embodiment, antisense oligonucleotide target SEQ ID NO:2.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:2 and SEQ ID NO:2 at least 90% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:2 and SEQ ID NO:2 at least 95% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:2 and SEQ ID NO:2100% complementation.In some such embodiment, antisense oligonucleotide comprises the nucleotide sequence that is selected from the listed nucleotide sequence of table 6.

Table 6: the antisense sequences of target NT_032977.8 (SEQ ID NO:2)

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				4	2274	2293	GCGCGGAATCCTGGCTGGGA
5	2381	2400	GAGGAGACCTAGAGGCCGTG
				159	2433	2452	GCCTGGAGCTGACGGTGCCC
160	2437	2456	GACCGCCTGGAGCTGACGGT
				6	2439	2458	AGGACCGCCTGGAGCTGACG
162	2545	2564	AAGGCTAGCACCAGCTCCTC
				163	2546	2565	CAAGGCTAGCACCAGCTCCT
164	2547	2566	GCAAGGCTAGCACCAGCTCC
				165	2548	2567	CGCAAGGCTAGCACCAGCTC
7	2549	2568	ACGCAAGGCTAGCACCAGCT
				166	2550	2569	AACGCAAGGCTAGCACCAGC
167	2551	2570	GAACGCAAGGCTAGCACCAG
				168	2552	2571	GGAACGCAAGGCTAGCACCA
169	2553	2572	CGGAACGCAAGGCTAGCACC
				8	2556	2575	CCTCGGAACGCAAGGCTAGC
170	2560	2579	TCCTCCTCGGAACGCAAGGC
				171	2585	2604	GTGCTCGGGTGCTTCGGCCA
172	2605	2624	TGGAAGGTGGCTGTGGTTCC
				9	2619	2638	CCTTGGCGCAGCGGTGGAAG
107	3056	3075	CCCACTATAATGGCAAGCCC
				80	4306	4325	AACCCAGTTCTAATGCACCT
106	5140	5159	CCAGTCAGAGTAGAACAGAG
				102	5590	5609	ATGTGCAGAGATCAATCACA
121	5599	5618	GGAGCCTACATGTGCAGAGA
				94	5667	5686	AGCATGGCACCAGCATCTGC
176	6444	6463	CGTAGGTGCCAGGCAACCTC
				177	6482	6501	TGACTGCGAGAGGTGGGTCT
178	6492	6511	CAGTGCGCTCTGACTGCGAG
				179	6494	6513	GGCAGTGCGCTCTGACTGCG
180	6496	6515	CGGGCAGTGCGCTCTGACTG
				10	6498	6517	GGCGGGCAGTGCGCTCTGAC

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				181	6499	6518	CGGCGGGCAGTGCGCTCTGA
182	6528	6547	ATCCCCGGCGGGCAGCCTGG
				183	6532	6551	AGGTATCCCCGGCGGGCAGC
184	6534	6553	TGAGGTATCCCCGGCGGGCA
				185	6535	6554	GTGAGGTATCCCCGGCGGGC
186	6536	6555	GGTGAGGTATCCCCGGCGGG
				11	6537	6556	TGGTGAGGTATCCCCGGCGG
187	6538	6557	TTGGTGAGGTATCCCCGGCG
				188	6539	6558	CTTGGTGAGGTATCCCCGGC
189	6540	6559	TCTTGGTGAGGTATCCCCGG
				190	6541	6560	ATCTTGGTGAGGTATCCCCG
191	6542	6561	GATCTTGGTGAGGTATCCCC
				12	6543	6562	GGATCTTGGTGAGGTATCCC
192	6544	6563	AGGATCTTGGTGAGGTATCC
				193	6546	6565	GCAGGATCTTGGTGAGGTAT
194	6548	6567	ATGCAGGATCTTGGTGAGGT
				195	6550	6569	ACATGCAGGATCTTGGTGAG
13	6552	6571	AGACATGCAGGATCTTGGTG
				196	6554	6573	GAAGACATGCAGGATCTTGG
14	6557	6576	ATGGAAGACATGCAGGATCT
				197	6565	6584	AGAAGGCCATGGAAGACATG
198	6575	6594	GAAGCCAGGAAGAAGGCCAT
				15	6583	6602	TTCACCAGGAAGCCAGGAAG
199	6585	6604	TCTTCACCAGGAAGCCAGGA
				16	6588	6607	TCATCTTCACCAGGAAGCCA
200	6590	6609	ACTCATCTTCACCAGGAAGC
				201	6592	6611	CCACTCATCTTCACCAGGAA
202	6594	6613	CGCCACTCATCTTCACCAGG
				203	6596	6615	GTCGCCACTCATCTTCACCA
204	6598	6617	AGGTCGCCACTCATCTTCAC
				205	6600	6619	GCAGGTCGCCACTCATCTTC
206	6602	6621	CAGCAGGTCGCCACTCATCT
				207	6604	6623	TCCAGCAGGTCGCCACTCAT
108	6652	6671	CCCAGCCCTATCAGGAAGTG
				144	7099	7118	TGACATCCAGGAGGGAGGAG
91	7556	7575	AGACTGATGGAAGGCATTGA
				131	7565	7584	GTGTTGAGCAGACTGATGGA
145	8836	8855	TGACATCTTGTCTGGGAGCC
				90	8948	8967	AGACTAGGAGCCTGAGTTTT
125	9099	9118	GGCCTGCAGAAGCCAGAGAG
				17	9130	9149	CCTCGATGTAGTCGACATGG
209	9149	9168	GCAAAGACAGAGGAGTCCTC
				210	9207	9226	TTCATCCGCCCGGTACCGTG
211	9209	9228	TATTCATCCGCCCGGTACCG
				18	9210	9229	GTATTCATCCGCCCGGTACC
212	9212	9231	TGGTATTCATCCGCCCGGTA
				213	9214	9233	GCTGGTATTCATCCGCCCGG
214	9216	9235	GGGCTGGTATTCATCCGCCC
				148	10252	10271	TGGCAGCAACTCAGACATAT
127	10633	10652	GGTGGTAATTTGTCACAGCA
				84	11308	11327	AAGGTCACACAGTTAAGAGT
79	11472	11491	AAATGCAGGGCTAAAATCAC
				88	12715	12734	ACTGGATACATTGGCAGACA
111	12928	12947	CTAGAGGAACCACTAGATAT
				85	13681	13700	ACAAATTCCCAGACTCAGCA
100	13746	13765	ATCTCAGGACAGGTGAGCAA
				116	13760	13779	GAGTAGAGATTCTCATCTCA

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				129	13816	13835	GTGCCATCTGAACAGCACCT
117	13828	13847	GAGTCTTCTGAAGTGCCATC
				81	13903	13922	AAGCAGGGCCTCAGGTGGAA
110	13926	13945	CCTGGAACCCCTGCAGCCAG
				152	13977	13996	TTCAGGCAGGTTGCTGCTAG
83	13986	14005	AAGGAAGACTTCAGGCAGGT
				140	13998	14017	TCAGCCAGGCCAAAGGAAGA
137	14112	14131	TAGGGAGAGCTCACAGATGC
				136	14122	14141	TAGGAGAAAGTAGGGAGAGC
132	14179	14198	TAAAAGCTGCAAGAGACTCA
				139	14267	14286	TCAGAGAAAACAGTCACCGA
92	14397	14416	AGAGACAGGAAGCTGCAGCT
				142	14404	14423	TCATTTTAGAGACAGGAAGC
113	14441	14460	GAATAACAGTGATGTCTGGC
				138	14494	14513	TCACAGCTCACCGAGTCTGC
98	14524	14543	AGTGTAAAATAAAGCCCCTA
				96	14601	14620	AGGACCCAAGTCATCCTGCT
124	14631	14650	GGCCATCAGCTGGCAATGCT
				82	14670	14689	AAGGAAAGGGAGGCCTAGAG
133	14675	14694	TAGACAAGGAAAGGGAGGCC
				103	14681	14700	ATTTCATAGACAAGGAAAGG
155	14801	14820	CTTATAGTTAACACACAGAA
				156	14809	14828	AAGTCAACCTTATAGTTAAC
215	14877	14896	ATACACCTCCACCAGGCTGC
				216	14888	14907	GTGTCTAGGAGATACACCTC
19	14891	14910	CTGGTGTCTAGGAGATACAC
				217	14893	14912	TGCTGGTGTCTAGGAGATAC
20	14896	14915	GTATGCTGGTGTCTAGGAGA
				21	14916	14935	GATTTCCCGGTGGTCACTCT
218	14918	14937	TCGATTTCCCGGTGGTCACT
				219	14919	14938	CTCGATTTCCCGGTGGTCAC
220	14920	14939	CCTCGATTTCCCGGTGGTCA
				221	14921	14940	CCCTCGATTTCCCGGTGGTC
22	14922	14941	GCCCTCGATTTCCCGGTGGT
				222	14923	14942	TGCCCTCGATTTCCCGGTGG
223	14924	14943	CTGCCCTCGATTTCCCGGTG
				224	14925	14944	CCTGCCCTCGATTTCCCGGT
225	14926	14945	CCCTGCCCTCGATTTCCCGG
				226	14930	14949	ATGACCCTGCCCTCGATTTC
227	14932	14951	CCATGACCCTGCCCTCGATT
				228	14934	14953	GACCATGACCCTGCCCTCGA
23	14936	14955	GTGACCATGACCCTGCCCTC
				229	14938	14957	CGGTGACCATGACCCTGCCC
230	14940	14959	GTCGGTGACCATGACCCTGC
				231	14942	14961	AAGTCGGTGACCATGACCCT
232	14944	14963	CGAAGTCGGTGACCATGACC
				24	14946	14965	CTCGAAGTCGGTGACCATGA
233	14954	14973	GGCACATTCTCGAAGTCGGT
				25	14979	14998	GTGGAAGCGGGTCCCGTCCT
235	15254	15273	GGTGGGTGCCATGACTGTCA
				236	15257	15276	CCAGGTGGGTGCCATGACTG
237	15261	15280	CCTGCCAGGTGGGTGCCATG
				26	15264	15283	ACCCCTGCCAGGTGGGTGCC
238	15266	15285	CCACCCCTGCCAGGTGGGTG
				27	15269	15288	TGACCACCCCTGCCAGGTGG
239	15271	15290	GCTGACCACCCCTGCCAGGT
				240	15279	15298	TCCCGGCCGCTGACCACCCC

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				241	15283	15302	GGCATCCCGGCCGCTGACCA
242	15286	15305	GCCGGCATCCCGGCCGCTGA
				243	15291	15310	GCCACGCCGGCATCCCGGCC
244	15292	15311	GGCCACGCCGGCATCCCGGC
				245	15293	15312	TGGCCACGCCGGCATCCCGG
246	15294	15313	TTGGCCACGCCGGCATCCCG
				247	15295	15314	CTTGGCCACGCCGGCATCCC
248	15296	15315	CCTTGGCCACGCCGGCATCC
				249	15297	15316	CCCTTGGCCACGCCGGCATC
28	15298	15317	ACCCTTGGCCACGCCGGCAT
				447	15298	15317	ACCCTTGGTCACGCCGGCAT
250	15299	15318	CACCCTTGGCCACGCCGGCA
				251	15300	15319	GCACCCTTGGCCACGCCGGC
252	15301	15320	GGCACCCTTGGCCACGCCGG
				253	15302	15321	TGGCACCCTTGGCCACGCCG
254	15303	15322	CTGGCACCCTTGGCCACGCC
				255	15304	15323	GCTGGCACCCTTGGCCACGC
256	15309	15328	CGCATGCTGGCACCCTTGGC
				257	15330	15349	CAGTTGAGCACGCGCAGGCT
258	15332	15351	GGCAGTTGAGCACGCGCAGG
				29	15334	15353	TTGGCAGTTGAGCACGCGCA
259	15336	15355	CCTTGGCAGTTGAGCACGCG
				30	15339	15358	TTCCCTTGGCAGTTGAGCAC
260	15341	15360	CCTTCCCTTGGCAGTTGAGC
				261	15345	15364	GTGCCCTTCCCTTGGCAGTT
262	15347	15366	CCGTGCCCTTCCCTTGGCAG
				263	15358	15377	GGTGCCGCTAACCGTGCCCT
86	15471	15490	ACAGCATTCTTGGTTAGGAG
				97	16134	16153	AGTCAAGCTGCTGCCCAGAG
120	16668	16687	GCTAGTTATTAAGCACCTGC
				150	17267	17286	TGTGAGCTCTGGCCCAGTGG
115	18377	18396	GAGTAAGGCAGGTTACTCTC
				134	18408	18427	TAGATGTGACTAACATTTAA
157	18561	18580	AGGAACAAAGCCAAGGTCAC
				266	18591	18610	TGGCTTTTCCGAATAAACTC
32	18593	18612	GCTGGCTTTTCCGAATAAAC
				267	18595	18614	CAGCTGGCTTTTCCGAATAA
268	18597	18616	ACCAGCTGGCTTTTCCGAAT
				269	18599	18618	GGACCAGCTGGCTTTTCCGA
270	18603	18622	GGCTGGACCAGCTGGCTTTT
				271	18614	18633	GTGGCCCCACAGGCTGGACC
272	18627	18646	AGCAGCACCACCAGTGGCCC
				273	18649	18668	GCTGTACCCACCCGCCAGGG
274	18695	18714	CGACCCCAGCCCTCGCCAGG
				33	18705	18724	GTGACCAGCACGACCCCAGC
275	18707	18726	CGGTGACCAGCACGACCCCA
				276	18709	18728	AGCGGTGACCAGCACGACCC
277	18711	18730	GCAGCGGTGACCAGCACGAC
				278	18713	18732	CGGCAGCGGTGACCAGCACG
279	18714	18733	CCGGCAGCGGTGACCAGCAC
				280	18717	18736	TTGCCGGCAGCGGTGACCAG
281	18719	18738	AGTTGCCGGCAGCGGTGACC
				282	18721	18740	GAAGTTGCCGGCAGCGGTGA
283	18723	18742	CGGAAGTTGCCGGCAGCGGT
				284	18725	18744	CCCGGAAGTTGCCGGCAGCG
285	18727	18746	GTCCCGGAAGTTGCCGGCAG
				105	19203	19222	CACATTAGCCTTGCTCAAGT
151	19913	19932	TGTGATGACCTGGAAAGGTG

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				288	19931	19950	GGCATTGGTGGCCCCAACTG
149	19933	19952	TGGGCATTGGTGGCCCCAAC
				289	19941	19960	GCTGGTCTTGGGCATTGGTG
290	19954	19973	CCCAGGGTCACCGGCTGGTC
				291	19956	19975	TCCCCAGGGTCACCGGCTGG
292	19958	19977	AGTCCCCAGGGTCACCGGCT
				293	19960	19979	AAAGTCCCCAGGGTCACCGG
34	19962	19981	CCAAAGTCCCCAGGGTCACC
				294	19964	19983	CCCCAAAGTCCCCAGGGTCA
128	19966	19985	GTCCCCAAAGTCCCCAGGGT
				295	19969	19988	TTGGTCCCCAAAGTCCCCAG
35	19971	19990	AGTTGGTCCCCAAAGTCCCC
				296	19973	19992	AAAGTTGGTCCCCAAAGTCC
36	19976	19995	GCCAAAGTTGGTCCCCAAAG
				297	19978	19997	CGGCCAAAGTTGGTCCCCAA
298	19980	19999	AGCGGCCAAAGTTGGTCCCC
				299	19982	20001	ACAGCGGCCAAAGTTGGTCC
300	19984	20003	ACACAGCGGCCAAAGTTGGT
				301	19986	20005	CCACACAGCGGCCAAAGTTG
37	19988	20007	GTCCACACAGCGGCCAAAGT
				302	19990	20009	AGGTCCACACAGCGGCCAAA
303	19992	20011	AGAGGTCCACACAGCGGCCA
				304	19994	20013	AAAGAGGTCCACACAGCGGC
38	19997	20016	GGCAAAGAGGTCCACACAGC
				305	20016	20035	CAATGATGTCCTCCCCTGGG
306	20023	20042	GAGGCACCAATGATGTCCTC
				39	20025	20044	TGGAGGCACCAATGATGTCC
307	20027	20046	GCTGGAGGCACCAATGATGT
				308	20029	20048	TCGCTGGAGGCACCAATGAT
309	20031	20050	AGTCGCTGGAGGCACCAATG
				310	20033	20052	GCAGTCGCTGGAGGCACCAA
40	20036	20055	GCTGCAGTCGCTGGAGGCAC
				311	20038	20057	GTGCTGCAGTCGCTGGAGGC
312	20040	20059	AGGTGCTGCAGTCGCTGGAG
				313	20042	20061	GCAGGTGCTGCAGTCGCTGG
314	20043	20062	AGCAGGTGCTGCAGTCGCTG
				315	20045	20064	AAAGCAGGTGCTGCAGTCGC
41	20047	20066	ACAAAGCAGGTGCTGCAGTC
				316	20049	20068	ACACAAAGCAGGTGCTGCAG
317	20051	20070	TGACACAAAGCAGGTGCTGC
				318	20061	20080	TCCCACTCTGTGACACAAAG
158	20100	20119	GTGGTGACTTACCAGCCACG
				109	20188	20207	CCCCTGCACAGAGCCTGGCA
141	20624	20643	TCATGGCTGCAATGCCTGGT
				320	20629	20648	CAGCATCATGGCTGCAATGC
321	20631	20650	GACAGCATCATGGCTGCAAT
				322	20633	20652	CAGACAGCATCATGGCTGCA
43	20635	20654	GGCAGACAGCATCATGGCTG
				323	20637	20656	TCGGCAGACAGCATCATGGC
324	20639	20658	GCTCGGCAGACAGCATCATG
				325	20641	20660	CGGCTCGGCAGACAGCATCA
326	20643	20662	TCCGGCTCGGCAGACAGCAT
				327	20657	20676	CGGCCAGGGTGAGCTCCGGC
328	20670	20689	CTCTGCCTCAACTCGGCCAG
				329	20672	20691	GTCTCTGCCTCAACTCGGCC
330	20674	20693	CAGTCTCTGCCTCAACTCGG
				331	20676	20695	ATCAGTCTCTGCCTCAACTC
332	20678	20697	GGATCAGTCTCTGCCTCAAC
				333	20680	20699	GTGGATCAGTCTCTGCCTCA

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				334	20682	20701	AAGTGGATCAGTCTCTGCCT
44	20683	20702	GAAGTGGATCAGTCTCTGCC
				335	20685	20704	GAGAAGTGGATCAGTCTCTG
336	20687	20706	CAGAGAAGTGGATCAGTCTC
				337	20689	20708	GGCAGAGAAGTGGATCAGTC
45	20691	20710	TTGGCAGAGAAGTGGATCAG
				338	20693	20712	CTTTGGCAGAGAAGTGGATC
46	20696	20715	CATCTTTGGCAGAGAAGTGG
				339	20698	20717	GACATCTTTGGCAGAGAAGT
340	20700	20719	ATGACATCTTTGGCAGAGAA
				47	20702	20721	TGATGACATCTTTGGCAGAG
341	20704	20723	ATTGATGACATCTTTGGCAG
				342	20706	20725	TCATTGATGACATCTTTGGC
48	20709	20728	GCCTCATTGATGACATCTTT
				343	20711	20730	AGGCCTCATTGATGACATCT
344	20713	20732	CCAGGCCTCATTGATGACAT
				345	20715	20734	AACCAGGCCTCATTGATGAC
346	20717	20736	GGAACCAGGCCTCATTGATG
				347	20718	20737	GGGAACCAGGCCTCATTGAT
348	20719	20738	AGGGAACCAGGCCTCATTGA
				349	20720	20739	CAGGGAACCAGGCCTCATTG
49	20721	20740	TCAGGGAACCAGGCCTCATT
				350	20722	20741	CTCAGGGAACCAGGCCTCAT
351	20723	20742	CCTCAGGGAACCAGGCCTCA
				352	20724	20743	TCCTCAGGGAACCAGGCCTC
353	20725	20744	GTCCTCAGGGAACCAGGCCT
				50	20726	20745	GGTCCTCAGGGAACCAGGCC
354	20727	20746	TGGTCCTCAGGGAACCAGGC
				355	20728	20747	CTGGTCCTCAGGGAACCAGG
356	20729	20748	GCTGGTCCTCAGGGAACCAG
				357	20730	20749	CGCTGGTCCTCAGGGAACCA
87	20733	20752	ACCCGCTGGTCCTCAGGGAA
				358	20735	20754	GTACCCGCTGGTCCTCAGGG
359	20737	20756	CAGTACCCGCTGGTCCTCAG
				51	20740	20759	GGTCAGTACCCGCTGGTCCT
119	20762	20781	GCAGGGCGGCCACCAGGTTG
				360	20785	20804	ACCTGCCCCATGGGTGCTGG
93	20995	21014	AGAGAGGAGGGCTTAAAGAA
				95	21082	21101	AGCTGCCAACCTGCAAAAAG
361	21088	21107	CAAAACAGCTGCCAACCTGC
				53	21091	21110	CTGCAAAACAGCTGCCAACC
362	21093	21112	TCCTGCAAAACAGCTGCCAA
				363	21095	21114	AGTCCTGCAAAACAGCTGCC
364	21106	21125	GCTGACCATACAGTCCTGCA
				365	21118	21137	GGCCCCGAGTGTGCTGACCA
54	21121	21140	GTAGGCCCCGAGTGTGCTGA
				366	21123	21142	GTGTAGGCCCCGAGTGTGCT
367	21125	21144	CCGTGTAGGCCCCGAGTGTG
				368	21127	21146	ATCCGTGTAGGCCCCGAGTG
369	21129	21148	CCATCCGTGTAGGCCCCGAG
				370	21131	21150	GGCCATCCGTGTAGGCCCCG
371	21133	21152	GTGGCCATCCGTGTAGGCCC
				372	21181	21200	CTGGAGCAGCTCAGCAGCTC
460	21181	21194	CAGCTCAGCAGCTC
				373	21183	21202	AACTGGAGCAGCTCAGCAGC
55	21186	21205	AGAAACTGGAGCAGCTCAGC
				374	21188	21207	GGAGAAACTGGAGCAGCTCA

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				375	21190	21209	CTGGAGAAACTGGAGCAGCT
56	21192	21211	TCCTGGAGAAACTGGAGCAG
				143	21481	21500	TGAAAATCCATCCAGCACTG
89	21589	21608	AGAACCATGGAGCACCTGAG
				448	21692	21711	CTGCCCTTCCACCAAAATGC
449	21693	21712	ACTGCCCTTCCACCAAAATG
				450	21694	21713	CACTGCCCTTCCACCAAAAT
451	21695	21714	GCACTGCCCTTCCACCAAAA
				123	21696	21715	GGCACTGCCCTTCCACCAAA
452	21697	21716	GGGCACTGCCCTTCCACCAA
				453	21698	21717	TGGGCACTGCCCTTCCACCA
454	21699	21718	CTGGGCACTGCCCTTCCACC
				455	21700	21719	GCTGGGCACTGCCCTTCCAC
57	22096	22115	CGTTGTGGGCCCGGCAGACC
				376	22133	22152	CACCTGGCAATGGCGTAGAC
377	22134	22153	GCACCTGGCAATGGCGTAGA
				378	22135	22154	AGCACCTGGCAATGGCGTAG
379	22136	22155	CAGCACCTGGCAATGGCGTA
				380	22137	22156	GCAGCACCTGGCAATGGCGT
381	22138	22157	GGCAGCACCTGGCAATGGCG
				382	22139	22158	AGGCAGCACCTGGCAATGGC
383	22140	22159	CAGGCAGCACCTGGCAATGG
				384	22141	22160	GCAGGCAGCACCTGGCAATG
58	22142	22161	AGCAGGCAGCACCTGGCAAT
				385	22143	22162	TAGCAGGCAGCACCTGGCAA
386	22144	22163	GTAGCAGGCAGCACCTGGCA
				387	22189	22208	TGGCCTCAGCTGGTGGAGCT
388	22199	22218	GTCCCCATGCTGGCCTCAGC
				389	22200	22219	GGTCCCCATGCTGGCCTCAG
390	22201	22220	GGGTCCCCATGCTGGCCTCA
				391	22202	22221	CGGGTCCCCATGCTGGCCTC
392	22203	22222	ACGGGTCCCCATGCTGGCCT
				59	22204	22223	CACGGGTCCCCATGCTGGCC
393	22205	22224	ACACGGGTCCCCATGCTGGC
				394	22206	22225	GACACGGGTCCCCATGCTGG
395	22207	22226	GGACACGGGTCCCCATGCTG
				396	22208	22227	TGGACACGGGTCCCCATGCT
397	22209	22228	GTGGACACGGGTCCCCATGC
				398	22210	22229	AGTGGACACGGGTCCCCATG
399	22211	22230	CAGTGGACACGGGTCCCCAT
				400	22212	22231	GCAGTGGACACGGGTCCCCA
401	22213	22232	GGCAGTGGACACGGGTCCCC
				402	22214	22233	TGGCAGTGGACACGGGTCCC
403	22215	22234	GTGGCAGTGGACACGGGTCC
				404	22216	22235	GGTGGCAGTGGACACGGGTC
405	22217	22236	TGGTGGCAGTGGACACGGGT
				406	22220	22239	TGTTGGTGGCAGTGGACACG
126	22292	22311	GGTGCATAAGGAGAAAGAGA
				408	23985	24004	GTGCCAAGGTCCTCCACCTC
409	24005	24024	TCAGCACAGGCGGCTTGTGG
				410	24035	24054	CCACGCACTGGTTGGGCTGA
60	24095	24114	CTTTGCATTCCAGACCTGGG
				411	24096	24115	ACTTTGCATTCCAGACCTGG
412	24097	24116	GACTTTGCATTCCAGACCTG
				413	24098	24117	TGACTTTGCATTCCAGACCT
414	24099	24118	TTGACTTTGCATTCCAGACC
				61	24100	24119	CTTGACTTTGCATTCCAGAC
415	24102	24121	TCCTTGACTTTGCATTCCAG
				416	24115	24134	CGGGATTCCATGCTCCTTGA

SEQ ID NO	5 ' initiation site to SEQ ID NO:2	3 ' initiation site to SEQ ID NO:2	Sequence (5 ' to 3 ')
				147	24858	24877	TGAGTTCATTTAAGAGTGGA
118	24907	24926	GCACCATCCAGACCAGAATC
				114	25413	25432	GAGAGGTTCAGATCCAGGCC
418	25994	26013	GGAGGGCACTGCAGCCAGTC
				419	26112	26131	CAGATGGCAACGGCTGTCAC
420	26113	26132	GCAGATGGCAACGGCTGTCA
				421	26114	26133	AGCAGATGGCAACGGCTGTC
422	26115	26134	CAGCAGATGGCAACGGCTGT
				423	26116	26135	GCAGCAGATGGCAACGGCTG
62	26117	26136	GGCAGCAGATGGCAACGGCT
				424	26118	26137	CGGCAGCAGATGGCAACGGC
425	26119	26138	CCGGCAGCAGATGGCAACGG
				426	26120	26139	TCCGGCAGCAGATGGCAACG
427	26121	26140	CTCCGGCAGCAGATGGCAAC
				428	26122	26141	GCTCCGGCAGCAGATGGCAA
429	26132	26151	CCAGGTGCCGGCTCCGGCAG
				430	26142	26161	GAGGCCTGCGCCAGGTGCCG
154	26217	26236	TTTTAAAGCTCAGCCCCAGC
				63	26222	26241	AACCATTTTAAAGCTCAGCC
64	26311	26330	TCAAGGGCCAGGCCAGCAGC
				65	26316	26335	CCCACTCAAGGGCCAGGCCA
122	26389	26408	GGAGGGAGCTTCCTGGCACC
				66	26404	26423	ATGCCCCACAGTGAGGGAGG
67	26413	26432	AATGGTGAAATGCCCCACAG
				153	26456	26475	TTGGGAGCAGCTGGCAGCAC
68	26557	26576	CATGGGAAGAATCCTGCCTC
				431	26635	26654	ATGAGGGCCATCAGCACCTT
432	26636	26655	GATGAGGGCCATCAGCACCT
				433	26637	26656	AGATGAGGGCCATCAGCACC
434	26638	26657	GAGATGAGGGCCATCAGCAC
				69	26639	26658	GGAGATGAGGGCCATCAGCA
435	26640	26659	TGGAGATGAGGGCCATCAGC
				436	26641	26660	CTGGAGATGAGGGCCATCAG
437	26642	26661	GCTGGAGATGAGGGCCATCA
				438	26643	26662	AGCTGGAGATGAGGGCCATC
461	26684	26697	TTAATCAGGGAGCC
				70	26707	26726	TAGATGCCATCCAGAAAGCT
439	26709	26728	GCTAGATGCCATCCAGAAAG
				440	26710	26729	GGCTAGATGCCATCCAGAAA
441	26711	26730	TGGCTAGATGCCATCCAGAA
				442	26712	26731	CTGGCTAGATGCCATCCAGA
71	26713	26732	TCTGGCTAGATGCCATCCAG
				443	26714	26733	CTCTGGCTAGATGCCATCCA
444	26715	26734	CCTCTGGCTAGATGCCATCC
				445	26716	26735	GCCTCTGGCTAGATGCCATC
446	26717	26736	AGCCTCTGGCTAGATGCCAT
				72	26790	26809	GGCATAGAGCAGAGTAAAGG
73	26795	26814	AGCCTGGCATAGAGCAGAGT
				135	26801	26820	TAGCACAGCCTGGCATAGAG
112	27034	27053	GAAGAGGCTTGGCTTCAGAG
				74	27040	27059	AAGTAAGAAGAGGCTTGGCT
75	27244	27263	GCTCAAGGAGGGACAGTTGT
				76	27279	27298	AAAGATAAATGTCTGCTTGC
77	27284	27303	ACCCAAAAGATAAATGTCTG
				78	27350	27369	TCTTCAAGTTACAAAAGCAA
99	27357	27376	ATAAATATCTTCAAGTTACA

In certain embodiments, breach polymers antisense compounds target PCSK9 nucleic acid.In some such embodiment, breach polymers antisense compounds target SEQ ID NO:2.In some such embodiment, illustrative nucleotide sequence has 5-10-5 breach polymers motif in the table 6.Table 7 illustration the breach polymers antisense compounds of target SEQ ID NO:2, it has the 5-10-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 7: the breach polymers antisense compounds of target SEQ ID NO:2 with 5-10-5 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							395149	5-10-5	4	2274	2293	0	GCGCGGAATCCTGGCTGGGA
395150	5-10-5	5	2381	2400	0	GAGGAGACCTAGAGGCCGTG
							395151	5-10-5	6	2439	2458	0	AGGACCGCCTGGAGCTGACG
395152	5-10-5	7	2549	2568	0	ACGCAAGGCTAGCACCAGCT
							399793	5-10-5	8	2556	2575	0	CCTCGGAACGCAAGGCTAGC
395153	5-10-5	9	2619	2638	0	CCTTGGCGCAGCGGTGGAAG
							399837	5-10-5	107	3056	3075	0	CCCACTATAATGGCAAGCCC
399838	5-10-5	80	4306	4325	0	AACCCAGTTCTAATGCACCT
							399839	5-10-5	106	5140	5159	0	CCAGTCAGAGTAGAACAGAG
395221	5-10-5	102	5590	5609	0	ATGTGCAGAGATCAATCACA
							399840	5-10-5	121	5599	5618	0	GGAGCCTACATGTGCAGAGA
399841	5-10-5	94	5667	5686	0	AGCATGGCACCAGCATCTGC
							395154	5-10-5	10	6498	6517	0	GGCGGGCAGTGCGCTCTGAC
395155	5-10-5	11	6537	6556	0	TGGTGAGGTATCCCCGGCGG
							399794	5-10-5	12	6543	6562	0	GGATCTTGGTGAGGTATCCC
399795	5-10-5	13	6552	6571	0	AGACATGCAGGATCTTGGTG
							395156	5-10-5	14	6557	6576	0	ATGGAAGACATGCAGGATCT
395157	5-10-5	15	6583	6602	0	TTCACCAGGAAGCCAGGAAG
							399796	5-10-5	16	6588	6607	0	TCATCTTCACCAGGAAGCCA
399842	5-10-5	108	6652	6671	0	CCCAGCCCTATCAGGAAGTG
							399843	5-10-5	144	7099	7118	0	TGACATCCAGGAGGGAGGAG
399844	5-10-5	91	7556	7575	0	AGACTGATGGAAGGCATTGA
							399845	5-10-5	131	7565	7584	0	GTGTTGAGCAGACTGATGGA
399846	5-10-5	145	8836	8855	0	TGACATCTTGTCTGGGAGCC
							399847	5-10-5	90	8948	8967	0	AGACTAGGAGCCTGAGTTTT
399848	5-10-5	125	9099	9118	0	GGCCTGCAGAAGCCAGAGAG
							395158	5-10-5	17	9130	9149	0	CCTCGATGTAGTCGACATGG
395159	5-10-5	18	9210	9229	0	GTATTCATCCGCCCGGTACC
							399849	5-10-5	148	10252	10271	0	TGGCAGCAACTCAGACATAT
395222	5-10-5	127	10633	10652	0	GGTGGTAATTTGTCACAGCA
							395223	5-10-5	84	11308	11327	0	AAGGTCACACAGTTAAGAGT
399850	5-10-5	79	11472	11491	0	AAATGCAGGGCTAAAATCAC
							399851	5-10-5	88	12715	12734	0	ACTGGATACATTGGCAGACA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399852	5-10-5	111	12928	12947	0	CTAGAGGAACCACTAGATAT
395201	5-10-5	85	13681	13700	0	ACAAATTCCCAGACTCAGCA
							399827	5-10-5	100	13746	13765	0	ATCTCAGGACAGGTGAGCAA
399828	5-10-5	116	13760	13779	0	GAGTAGAGATTCTCATCTCA
							395202	5-10-5	129	13816	13835	0	GTGCCATCTGAACAGCACCT
399829	5-10-5	117	13828	13847	0	GAGTCTTCTGAAGTGCCATC
							399830	5-10-5	81	13903	13922	0	AAGCAGGGCCTCAGGTGGAA
395203	5-10-5	110	13926	13945	0	CCTGGAACCCCTGCAGCCAG
							395204	5-10-5	152	13977	13996	0	TTCAGGCAGGTTGCTGCTAG
399831	5-10-5	83	13986	14005	0	AAGGAAGACTTCAGGCAGGT
							395205	5-10-5	140	13998	14017	0	TCAGCCAGGCCAAAGGAAGA
399832	5-10-5	137	14112	14131	0	TAGGGAGAGCTCACAGATGC
							395206	5-10-5	136	14122	14141	0	TAGGAGAAAGTAGGGAGAGC
395207	5-10-5	132	14179	14198	0	TAAAAGCTGCAAGAGACTCA
							395208	5-10-5	139	14267	14286	0	TCAGAGAAAACAGTCACCGA
399833	5-10-5	92	14397	14416	0	AGAGACAGGAAGCTGCAGCT
							395209	5-10-5	142	14404	14423	0	TCATTTTAGAGACAGGAAGC
395210	5-10-5	113	14441	14460	0	GAATAACAGTGATGTCTGGC
							395211	5-10-5	138	14494	14513	0	TCACAGCTCACCGAGTCTGC
395212	5-10-5	98	14524	14543	0	AGTGTAAAATAAAGCCCCTA
							395213	5-10-5	96	14601	14620	0	AGGACCCAAGTCATCCTGCT
395214	5-10-5	124	14631	14650	0	GGCCATCAGCTGGCAATGCT
							399834	5-10-5	82	14670	14689	0	AAGGAAAGGGAGGCCTAGAG
395215	5-10-5	133	14675	14694	0	TAGACAAGGAAAGGGAGGCC
							395216	5-10-5	103	14681	14700	0	ATTTCATAGACAAGGAAAGG
395217	5-10-5	155	14801	14820	0	CTTATAGTTAACACACAGAA
							399835	5-10-5	156	14809	14828	0	AAGTCAACCTTATAGTTAAC
395160	5-10-5	19	14891	14910	0	CTGGTGTCTAGGAGATACAC
							399797	5-10-5	20	14896	14915	0	GTATGCTGGTGTCTAGGAGA
395161	5-10-5	21	14916	14935	0	GATTTCCCGGTGGTCACTCT
							399798	5-10-5	22	14922	14941	0	GCCCTCGATTTCCCGGTGGT
399799	5-10-5	23	14936	14955	0	GTGACCATGACCCTGCCCTC
							395162	5-10-5	24	14946	14965	0	CTCGAAGTCGGTGACCATGA
395163	5-10-5	25	14979	14998	0	GTGGAAGCGGGTCCCGTCCT
							395164	5-10-5	26	15264	15283	0	ACCCCTGCCAGGTGGGTGCC
399800	5-10-5	27	15269	15288	0	TGACCACCCCTGCCAGGTGG
							395165	5-10-5	28	15298	15317	0	ACCCTTGGCCACGCCGGCAT
395166	5-10-5	29	15334	15353	0	TTGGCAGTTGAGCACGCGCA
							399801	5-10-5	30	15339	15358	0	TTCCCTTGGCAGTTGAGCAC
399853	5-10-5	86	15471	15490	0	ACAGCATTCTTGGTTAGGAG
							399854	5-10-5	97	16134	16153	0	AGTCAAGCTGCTGCCCAGAG
399855	5-10-5	120	16668	16687	0	GCTAGTTATTAAGCACCTGC
							399856	5-10-5	150	17267	17286	0	TGTGAGCTCTGGCCCAGTGG
399857	5-10-5	115	18377	18396	0	GAGTAAGGCAGGTTACTCTC
							399858	5-10-5	134	18408	18427	0	TAGATGTGACTAACATTTAA
395224	5-10-5	157	18561	18580	0	AGGAACAAAGCCAAGGTCAC
							395168	5-10-5	32	18593	18612	0	GCTGGCTTTTCCGAATAAAC
395169	5-10-5	33	18705	18724	0	GTGACCAGCACGACCCCAGC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399859	5-10-5	105	19203	19222	0	CACATTAGCCTTGCTCAAGT
399860	5-10-5	151	19913	19932	0	TGTGATGACCTGGAAAGGTG
							395170	5-10-5	149	19933	19952	0	TGGGCATTGGTGGCCCCAAC
395171	5-10-5	34	19962	19981	0	CCAAAGTCCCCAGGGTCACC
							395172	5-10-5	128	19966	19985	0	GTCCCCAAAGTCCCCAGGGT
399802	5-10-5	35	19971	19990	0	AGTTGGTCCCCAAAGTCCCC
							395173	5-10-5	36	19976	19995	0	GCCAAAGTTGGTCCCCAAAG
399803	5-10-5	37	19988	20007	0	GTCCACACAGCGGCCAAAGT
							395174	5-10-5	38	19997	20016	0	GGCAAAGAGGTCCACACAGC
395175	5-10-5	39	20025	20044	0	TGGAGGCACCAATGATGTCC
							399804	5-10-5	40	20036	20055	0	GCTGCAGTCGCTGGAGGCAC
399805	5-10-5	41	20047	20066	0	ACAAAGCAGGTGCTGCAGTC
							399861	5-10-5	158	20100	20119	0	GTGGTGACTTACCAGCCACG
399862	5-10-5	109	20188	20207	0	CCCCTGCACAGAGCCTGGCA
							399863	5-10-5	141	20624	20643	0	TCATGGCTGCAATGCCTGGT
399807	5-10-5	43	20635	20654	0	GGCAGACAGCATCATGGCTG
							399808	5-10-5	44	20683	20702	0	GAAGTGGATCAGTCTCTGCC
395177	5-10-5	45	20691	20710	0	TTGGCAGAGAAGTGGATCAG
							399809	5-10-5	46	20696	20715	0	CATCTTTGGCAGAGAAGTGG
399810	5-10-5	47	20702	20721	0	TGATGACATCTTTGGCAGAG
							399811	5-10-5	48	20709	20728	0	GCCTCATTGATGACATCTTT
399812	5-10-5	49	20721	20740	0	TCAGGGAACCAGGCCTCATT
							395178	5-10-5	50	20726	20745	0	GGTCCTCAGGGAACCAGGCC
395179	5-10-5	87	20733	20752	0	ACCCGCTGGTCCTCAGGGAA
							399813	5-10-5	51	20740	20759	0	GGTCAGTACCCGCTGGTCCT
395180	5-10-5	119	20762	20781	0	GCAGGGCGGCCACCAGGTTG
							399864	5-10-5	93	20995	21014	0	AGAGAGGAGGGCTTAAAGAA
399865	5-10-5	95	21082	21101	0	AGCTGCCAACCTGCAAAAAG
							399814	5-10-5	53	21091	21110	0	CTGCAAAACAGCTGCCAACC
395182	5-10-5	54	21121	21140	0	GTAGGCCCCGAGTGTGCTGA
							399815	5-10-5	55	21186	21205	0	AGAAACTGGAGCAGCTCAGC
399816	5-10-5	56	21192	21211	0	TCCTGGAGAAACTGGAGCAG
							399866	5-10-5	143	21481	21500	0	TGAAAATCCATCCAGCACTG
399867	5-10-5	89	21589	21608	0	AGAACCATGGAGCACCTGAG
							399868	5-10-5	123	21696	21715	0	GGCACTGCCCTTCCACCAAA
395183	5-10-5	57	22096	22115	0	CGTTGTGGGCCCGGCAGACC
							395184	5-10-5	58	22142	22161	0	AGCAGGCAGCACCTGGCAAT
395185	5-10-5	59	22204	22223	0	CACGGGTCCCCATGCTGGCC
							395225	5-10-5	126	22292	22311	0	GGTGCATAAGGAGAAAGAGA
395186	5-10-5	60	24095	24114	0	CTTTGCATTCCAGACCTGGG
							399817	5-10-5	61	24100	24119	0	CTTGACTTTGCATTCCAGAC
395226	5-10-5	147	24858	24877	0	TGAGTTCATTTAAGAGTGGA
							399869	5-10-5	118	24907	24926	0	GCACCATCCAGACCAGAATC
399870	5-10-5	114	25413	25432	0	GAGAGGTTCAGATCCAGGCC
							395187	5-10-5	62	26117	26136	0	GGCAGCAGATGGCAACGGCT
395188	5-10-5	154	26217	26236	0	TTTTAAAGCTCAGCCCCAGC
							399818	5-10-5	63	26222	26241	0	AACCATTTTAAAGCTCAGCC
395189	5-10-5	64	26311	26330	0	TCAAGGGCCAGGCCAGCAGC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399819	5-10-5	65	26316	26335	0	CCCACTCAAGGGCCAGGCCA
399820	5-10-5	122	26389	26408	0	GGAGGGAGCTTCCTGGCACC
							395190	5-10-5	66	26404	26423	0	ATGCCCCACAGTGAGGGAGG
395191	5-10-5	67	26413	26432	0	AATGGTGAAATGCCCCACAG
							395192	5-10-5	153	26456	26475	0	TTGGGAGCAGCTGGCAGCAC
395193	5-10-5	68	26557	26576	0	CATGGGAAGAATCCTGCCTC
							395194	5-10-5	69	26639	26658	0	GGAGATGAGGGCCATCAGCA
395195	5-10-5	70	26707	26726	0	TAGATGCCATCCAGAAAGCT
							399821	5-10-5	71	26713	26732	0	TCTGGCTAGATGCCATCCAG
395196	5-10-5	72	26790	26809	0	GGCATAGAGCAGAGTAAAGG
							399822	5-10-5	73	26795	26814	0	AGCCTGGCATAGAGCAGAGT
399823	5-10-5	135	26801	26820	0	TAGCACAGCCTGGCATAGAG
							395197	5-10-5	112	27034	27053	0	GAAGAGGCTTGGCTTCAGAG
399824	5-10-5	74	27040	27059	0	AAGTAAGAAGAGGCTTGGCT
							395198	5-10-5	75	27244	27263	0	GCTCAAGGAGGGACAGTTGT
395199	5-10-5	76	27279	27298	0	AAAGATAAATGTCTGCTTGC
							399825	5-10-5	77	27284	27303	0	ACCCAAAAGATAAATGTCTG
395200	5-10-5	78	27350	27369	0	TCTTCAAGTTACAAAAGCAA
							399826	5-10-5	99	27357	27376	0	ATAAATATCTTCAAGTTACA
405861	5-10-5	162	2545	2564	0	AAGGCTAGCACCAGCTCCTC
							405862	5-10-5	163	2546	2565	0	CAAGGCTAGCACCAGCTCCT
405863	5-10-5	164	2547	2566	0	GCAAGGCTAGCACCAGCTCC
							405864	5-10-5	165	2548	2567	0	CGCAAGGCTAGCACCAGCTC
405865	5-10-5	166	2550	2569	0	AACGCAAGGCTAGCACCAGC
							405866	5-10-5	167	2551	2570	0	GAACGCAAGGCTAGCACCAG
405867	5-10-5	168	2552	2571	0	GGAACGCAAGGCTAGCACCA
							405868	5-10-5	169	2553	2572	0	CGGAACGCAAGGCTAGCACC
405869	5-10-5	218	14918	14937	0	TCGATTTCCCGGTGGTCACT
							405870	5-10-5	219	14919	14938	0	CTCGATTTCCCGGTGGTCAC
405871	5-10-5	220	14920	14939	0	CCTCGATTTCCCGGTGGTCA
							405872	5-10-5	221	14921	14940	0	CCCTCGATTTCCCGGTGGTC
405873	5-10-5	222	14923	14942	0	TGCCCTCGATTTCCCGGTGG
							405874	5-10-5	223	14924	14943	0	CTGCCCTCGATTTCCCGGTG
405875	5-10-5	224	14925	14944	0	CCTGCCCTCGATTTCCCGGT
							405876	5-10-5	225	14926	14945	0	CCCTGCCCTCGATTTCCCGG
405877	5-10-5	246	15294	15313	0	TTGGCCACGCCGGCATCCCG
							405878	5-10-5	247	15295	15314	0	CTTGGCCACGCCGGCATCCC
405879	5-10-5	248	15296	15315	0	CCTTGGCCACGCCGGCATCC
							405880	5-10-5	249	15297	15316	0	CCCTTGGCCACGCCGGCATC
405881	5-10-5	250	15299	15318	0	CACCCTTGGCCACGCCGGCA
							405882	5-10-5	251	15300	15319	0	GCACCCTTGGCCACGCCGGC
405883	5-10-5	252	15301	15320	0	GGCACCCTTGGCCACGCCGG
							405884	5-10-5	253	15302	15321	0	TGGCACCCTTGGCCACGCCG
405885	5-10-5	346	20717	20736	0	GGAACCAGGCCTCATTGATG
							405886	5-10-5	347	20718	20737	0	GGGAACCAGGCCTCATTGAT
405887	5-10-5	348	20719	20738	0	AGGGAACCAGGCCTCATTGA
							405888	5-10-5	349	20720	20739	0	CAGGGAACCAGGCCTCATTG
405889	5-10-5	350	20722	20741	0	CTCAGGGAACCAGGCCTCAT

Isis number	Motif	SEQ ID NO	5 target sites on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							405890	5-10-5	351	20723	20742	0	CCTCAGGGAACCAGGCCTCA
405891	5-10-5	352	20724	20743	0	TCCTCAGGGAACCAGGCCTC
							405892	5-10-5	353	20725	20744	0	GTCCTCAGGGAACCAGGCCT
405893	5-10-5	431	26635	26654	0	ATGAGGGCCATCAGCACCTT
							405894	5-10-5	432	26636	26655	0	GATGAGGGCCATCAGCACCT
405895	5-10-5	433	26637	26656	0	AGATGAGGGCCATCAGCACC
							405896	5-10-5	434	26638	26657	0	GAGATGAGGGCCATCAGCAC
405897	5-10-5	435	26640	26659	0	TGGAGATGAGGGCCATCAGC
							405898	5-10-5	436	26641	26660	0	CTGGAGATGAGGGCCATCAG
405899	5-10-5	437	26642	26661	0	GCTGGAGATGAGGGCCATCA
							405900	5-10-5	438	26643	26662	0	AGCTGGAGATGAGGGCCATC
405901	5-10-5	439	26709	26728	0	GCTAGATGCCATCCAGAAAG
							405902	5-10-5	440	26710	26729	0	GGCTAGATGCCATCCAGAAA
405903	5-10-5	441	26711	26730	0	TGGCTAGATGCCATCCAGAA
							405904	5-10-5	442	26712	26731	0	CTGGCTAGATGCCATCCAGA
405905	5-10-5	443	26714	26733	0	CTCTGGCTAGATGCCATCCA
							405906	5-10-5	444	26715	26734	0	CCTCTGGCTAGATGCCATCC
405907	5-10-5	445	26716	26735	0	GCCTCTGGCTAGATGCCATC
							405908	5-10-5	446	26717	26736	0	AGCCTCTGGCTAGATGCCAT
405909	5-10-5	267	18595	18614	0	CAGCTGGCTTTTCCGAATAA
							405910	5-10-5	268	18597	18616	0	ACCAGCTGGCTTTTCCGAAT
405911	5-10-5	269	18599	18618	0	GGACCAGCTGGCTTTTCCGA
							405912	5-10-5	270	18603	18622	0	GGCTGGACCAGCTGGCTTTT
405913	5-10-5	275	18707	18726	0	CGGTGACCAGCACGACCCCA
							405914	5-10-5	276	18709	18728	0	AGCGGTGACCAGCACGACCC
405915	5-10-5	277	18711	18730	0	GCAGCGGTGACCAGCACGAC
							405916	5-10-5	278	18713	18732	0	CGGCAGCGGTGACCAGCACG
405917	5-10-5	280	18717	18736	0	TTGCCGGCAGCGGTGACCAG
							405918	5-10-5	281	18719	18738	0	AGTTGCCGGCAGCGGTGACC
405919	5-10-5	282	18721	18740	0	GAAGTTGCCGGCAGCGGTGA
							405920	5-10-5	283	18723	18742	0	CGGAAGTTGCCGGCAGCGGT
405921	5-10-5	284	18725	18744	0	CCCGGAAGTTGCCGGCAGCG
							405922	5-10-5	285	18727	18746	0	GTCCCGGAAGTTGCCGGCAG
405923	5-10-5	288	19931	19950	0	GGCATTGGTGGCCCCAACTG
							405924	5-10-5	290	19954	19973	0	CCCAGGGTCACCGGCTGGTC
405925	5-10-5	292	19958	19977	0	AGTCCCCAGGGTCACCGGCT
							405926	5-10-5	293	19960	19979	0	AAAGTCCCCAGGGTCACCGG
405927	5-10-5	294	19964	19983	0	CCCCAAAGTCCCCAGGGTCA
							405928	5-10-5	295	19969	19988	0	TTGGTCCCCAAAGTCCCCAG
405929	5-10-5	296	19973	19992	0	AAAGTTGGTCCCCAAAGTCC
							405930	5-10-5	297	19978	19997	0	CGGCCAAAGTTGGTCCCCAA
405931	5-10-5	298	19980	19999	0	AGCGGCCAAAGTTGGTCCCC
							405932	5-10-5	299	19982	20001	0	ACAGCGGCCAAAGTTGGTCC
405933	5-10-5	300	19984	20003	0	ACACAGCGGCCAAAGTTGGT
							405934	5-10-5	301	19986	20005	0	CCACACAGCGGCCAAAGTTG
405935	5-10-5	302	19990	20009	0	AGGTCCACACAGCGGCCAAA
							405936	5-10-5	304	19994	20013	0	AAAGAGGTCCACACAGCGGC
405937	5-10-5	306	20023	20042	0	GAGGCACCAATGATGTCCTC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							405938	5-10-5	307	20027	20046	0	GCTGGAGGCACCAATGATGT
405939	5-10-5	308	20029	20048	0	TCGCTGGAGGCACCAATGAT
							405940	5-10-5	309	20031	20050	0	AGTCGCTGGAGGCACCAATG
405941	5-10-5	310	20033	20052	0	GCAGTCGCTGGAGGCACCAA
							405942	5-10-5	311	20038	20057	0	GTGCTGCAGTCGCTGGAGGC
405943	5-10-5	312	20040	20059	0	AGGTGCTGCAGTCGCTGGAG
							405944	5-10-5	314	20043	20062	0	AGCAGGTGCTGCAGTCGCTG
405945	5-10-5	315	20045	20064	0	AAAGCAGGTGCTGCAGTCGC
							405946	5-10-5	316	20049	20068	0	ACACAAAGCAGGTGCTGCAG
405947	5-10-5	317	20051	20070	0	TGACACAAAGCAGGTGCTGC
							405949	5-10-5	320	20629	20648	0	CAGCATCATGGCTGCAATGC
405950	5-10-5	321	20631	20650	0	GACAGCATCATGGCTGCAAT
							405951	5-10-5	322	20633	20652	0	CAGACAGCATCATGGCTGCA
405952	5-10-5	323	20637	20656	0	TCGGCAGACAGCATCATGGC
							405953	5-10-5	325	20641	20660	0	CGGCTCGGCAGACAGCATCA
405954	5-10-5	326	20643	20662	0	TCCGGCTCGGCAGACAGCAT
							405955	5-10-5	328	20670	20689	0	CTCTGCCTCAACTCGGCCAG
405956	5-10-5	329	20672	20691	0	GTCTCTGCCTCAACTCGGCC
							405957	5-10-5	330	20674	20693	0	CAGTCTCTGCCTCAACTCGG
405958	5-10-5	331	20676	20695	0	ATCAGTCTCTGCCTCAACTC
							405959	5-10-5	332	20678	20697	0	GGATCAGTCTCTGCCTCAAC
405960	5-10-5	333	20680	20699	0	GTGGATCAGTCTCTGCCTCA
							405961	5-10-5	334	20682	20701	0	AAGTGGATCAGTCTCTGCCT
405962	5-10-5	335	20685	20704	0	GAGAAGTGGATCAGTCTCTG
							405963	5-10-5	337	20689	20708	0	GGCAGAGAAGTGGATCAGTC
405964	5-10-5	338	20693	20712	0	CTTTGGCAGAGAAGTGGATC
							405965	5-10-5	339	20698	20717	0	GACATCTTTGGCAGAGAAGT
405966	5-10-5	340	20700	20719	0	ATGACATCTTTGGCAGAGAA
							405967	5-10-5	341	20704	20723	0	ATTGATGACATCTTTGGCAG
405968	5-10-5	342	20706	20725	0	TCATTGATGACATCTTTGGC
							405969	5-10-5	343	20711	20730	0	AGGCCTCATTGATGACATCT
405970	5-10-5	344	20713	20732	0	CCAGGCCTCATTGATGACAT
							405971	5-10-5	355	20728	20747	0	CTGGTCCTCAGGGAACCAGG
405972	5-10-5	357	20730	20749	0	CGCTGGTCCTCAGGGAACCA
							405973	5-10-5	358	20735	20754	0	GTACCCGCTGGTCCTCAGGG
405974	5-10-5	359	20737	20756	0	CAGTACCCGCTGGTCCTCAG
							405975	5-10-5	361	21088	21107	0	CAAAACAGCTGCCAACCTGC
405976	5-10-5	362	21093	21112	0	TCCTGCAAAACAGCTGCCAA
							405977	5-10-5	363	21095	21114	0	AGTCCTGCAAAACAGCTGCC
405978	5-10-5	365	21118	21137	0	GGCCCCGAGTGTGCTGACCA
							405979	5-10-5	366	21123	21142	0	GTGTAGGCCCCGAGTGTGCT
405980	5-10-5	367	21125	21144	0	CCGTGTAGGCCCCGAGTGTG
							405981	5-10-5	368	21127	21146	0	ATCCGTGTAGGCCCCGAGTG
405982	5-10-5	370	21131	21150	0	GGCCATCCGTGTAGGCCCCG
							405983	5-10-5	371	21133	21152	0	GTGGCCATCCGTGTAGGCCC
405984	5-10-5	372	21181	21200	0	CTGGAGCAGCTCAGCAGCTC
							405985	5-10-5	373	21183	21202	0	AACTGGAGCAGCTCAGCAGC
405986	5-10-5	374	21188	21207	0	GGAGAAACTGGAGCAGCTCA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							405987	5-10-5	375	21190	21209	0	CTGGAGAAACTGGAGCAGCT
405988	5-10-5	381	22138	22157	0	GGCAGCACCTGGCAATGGCG
							405989	5-10-5	383	22140	22159	0	CAGGCAGCACCTGGCAATGG
405990	5-10-5	386	22144	22163	0	GTAGCAGGCAGCACCTGGCA
							405991	5-10-5	394	22206	22225	0	GACACGGGTCCCCATGCTGG
405992	5-10-5	396	22208	22227	0	TGGACACGGGTCCCCATGCT
							405993	5-10-5	398	22210	22229	0	AGTGGACACGGGTCCCCATG
405994	5-10-5	400	22212	22231	0	GCAGTGGACACGGGTCCCCA
							405995	5-10-5	402	22214	22233	0	TGGCAGTGGACACGGGTCCC
405996	5-10-5	412	24097	24116	0	GACTTTGCATTCCAGACCTG
							405997	5-10-5	415	24102	24121	0	TCCTTGACTTTGCATTCCAG
405998	5-10-5	426	26120	26139	0	TCCGGCAGCAGATGGCAACG
							405999	5-10-5	160	2437	2456	0	GACCGCCTGGAGCTGACGGT
406003	5-10-5	178	6492	6511	0	CAGTGCGCTCTGACTGCGAG
							406004	5-10-5	179	6494	6513	0	GGCAGTGCGCTCTGACTGCG
406005	5-10-5	180	6496	6515	0	CGGGCAGTGCGCTCTGACTG
							406006	5-10-5	181	6499	6518	0	CGGCGGGCAGTGCGCTCTGA
406007	5-10-5	183	6532	6551	0	AGGTATCCCCGGCGGGCAGC
							406008	5-10-5	188	6539	6558	0	CTTGGTGAGGTATCCCCGGC
406009	5-10-5	190	6541	6560	0	ATCTTGGTGAGGTATCCCCG
							406010	5-10-5	193	6546	6565	0	GCAGGATCTTGGTGAGGTAT
406011	5-10-5	194	6548	6567	0	ATGCAGGATCTTGGTGAGGT
							406012	5-10-5	195	6550	6569	0	ACATGCAGGATCTTGGTGAG
406013	5-10-5	196	6554	6573	0	GAAGACATGCAGGATCTTGG
							406014	5-10-5	199	6585	6604	0	TCTTCACCAGGAAGCCAGGA
406015	5-10-5	200	6590	6609	0	ACTCATCTTCACCAGGAAGC
							406016	5-10-5	201	6592	6611	0	CCACTCATCTTCACCAGGAA
406017	5-10-5	203	6596	6615	0	GTCGCCACTCATCTTCACCA
							406018	5-10-5	204	6598	6617	0	AGGTCGCCACTCATCTTCAC
406019	5-10-5	205	6600	6619	0	GCAGGTCGCCACTCATCTTC
							406020	5-10-5	206	6602	6621	0	CAGCAGGTCGCCACTCATCT
406021	5-10-5	210	9207	9226	0	TTCATCCGCCCGGTACCGTG
							406022	5-10-5	211	9209	9228	0	TATTCATCCGCCCGGTACCG
406023	5-10-5	212	9212	9231	0	TGGTATTCATCCGCCCGGTA
							406024	5-10-5	213	9214	9233	0	GCTGGTATTCATCCGCCCGG
406025	5-10-5	216	14888	14907	0	GTGTCTAGGAGATACACCTC
							406026	5-10-5	217	14893	14912	0	TGCTGGTGTCTAGGAGATAC
406027	5-10-5	226	14930	14949	0	ATGACCCTGCCCTCGATTTC
							406028	5-10-5	227	14932	14951	0	CCATGACCCTGCCCTCGATT
406029	5-10-5	228	14934	14953	0	GACCATGACCCTGCCCTCGA
							406030	5-10-5	229	14938	14957	0	CGGTGACCATGACCCTGCCC
406031	5-10-5	230	14940	14959	0	GTCGGTGACCATGACCCTGC
							406032	5-10-5	232	14944	14963	0	CGAAGTCGGTGACCATGACC
406033	5-10-5	237	15261	15280	0	CCTGCCAGGTGGGTGCCATG
							406034	5-10-5	238	15266	15285	0	CCACCCCTGCCAGGTGGGTG
406035	5-10-5	239	15271	15290	0	GCTGACCACCCCTGCCAGGT
							406036	5-10-5	241	15283	15302	0	GGCATCCCGGCCGCTGACCA
406037	5-10-5	242	15286	15305	0	GCCGGCATCCCGGCCGCTGA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							406038	5-10-5	245	15293	15312	0	TGGCCACGCCGGCATCCCGG
406039	5-10-5	257	15330	15349	0	CAGTTGAGCACGCGCAGGCT
							406040	5-10-5	258	15332	15351	0	GGCAGTTGAGCACGCGCAGG
406041	5-10-5	259	15336	15355	0	CCTTGGCAGTTGAGCACGCG
							406042	5-10-5	260	15341	15360	0	CCTTCCCTTGGCAGTTGAGC
406043	5-10-5	261	15345	15364	0	GTGCCCTTCCCTTGGCAGTT
							406044	5-10-5	262	15347	15366	0	CCGTGCCCTTCCCTTGGCAG
406045	5-10-5	266	18591	18610	0	TGGCTTTTCCGAATAAACTC
							406478	5-10-5	448	21692	21711	0	CTGCCCTTCCACCAAAATGC
406479	5-10-5	449	21693	21712	0	ACTGCCCTTCCACCAAAATG
							406480	5-10-5	450	21694	21713	0	CACTGCCCTTCCACCAAAAT
406481	5-10-5	451	21695	21714	0	GCACTGCCCTTCCACCAAAA
							406482	5-10-5	452	21697	21716	0	GGGCACTGCCCTTCCACCAA
406483	5-10-5	453	21698	21717	0	TGGGCACTGCCCTTCCACCA
							406484	5-10-5	454	21699	21718	0	CTGGGCACTGCCCTTCCACC
406485	5-10-5	455	21700	21719	0	GCTGGGCACTGCCCTTCCAC
							408653	5-10-5	354	20727	20746	0	TGGTCCTCAGGGAACCAGGC
409126	5-10-5	447	15298	15317	1	ACCCTTGGTCACGCCGGCAT
							410529	5-10-5	184	6534	6553	0	TGAGGTATCCCCGGCGGGCA
410530	5-10-5	185	6535	6554	0	GTGAGGTATCCCCGGCGGGC
							410531	5-10-5	186	6536	6555	0	GGTGAGGTATCCCCGGCGGG
410532	5-10-5	187	6538	6557	0	TTGGTGAGGTATCCCCGGCG
							410533	5-10-5	189	6540	6559	0	TCTTGGTGAGGTATCCCCGG
410534	5-10-5	191	6542	6561	0	GATCTTGGTGAGGTATCCCC
							410535	5-10-5	192	6544	6563	0	AGGATCTTGGTGAGGTATCC
410536	5-10-5	243	15291	15310	0	GCCACGCCGGCATCCCGGCC
							410537	5-10-5	244	15292	15311	0	GGCCACGCCGGCATCCCGGC
410538	5-10-5	254	15303	15322	0	CTGGCACCCTTGGCCACGCC
							410539	5-10-5	255	15304	15323	0	GCTGGCACCCTTGGCCACGC
410540	5-10-5	356	20729	20748	0	GCTGGTCCTCAGGGAACCAG
							410541	5-10-5	376	22133	22152	0	CACCTGGCAATGGCGTAGAC
410542	5-10-5	377	22134	22153	0	GCACCTGGCAATGGCGTAGA
							410543	5-10-5	378	22135	22154	0	AGCACCTGGCAATGGCGTAG
410544	5-10-5	379	22136	22155	0	CAGCACCTGGCAATGGCGTA
							410545	5-10-5	380	22137	22156	0	GCAGCACCTGGCAATGGCGT
410546	5-10-5	382	22139	22158	0	AGGCAGCACCTGGCAATGGC
							410547	5-10-5	384	22141	22160	0	GCAGGCAGCACCTGGCAATG
410548	5-10-5	385	22143	22162	0	TAGCAGGCAGCACCTGGCAA
							410549	5-10-5	388	22199	22218	0	GTCCCCATGCTGGCCTCAGC
410550	5-10-5	389	22200	22219	0	GGTCCCCATGCTGGCCTCAG
							410551	5-10-5	390	22201	22220	0	GGGTCCCCATGCTGGCCTCA
410552	5-10-5	391	22202	22221	0	CGGGTCCCCATGCTGGCCTC
							410553	5-10-5	392	22203	22222	0	ACGGGTCCCCATGCTGGCCT
410554	5-10-5	393	22205	22224	0	ACACGGGTCCCCATGCTGGC
							410555	5-10-5	395	22207	22226	0	GGACACGGGTCCCCATGCTG
410556	5-10-5	397	22209	22228	0	GTGGACACGGGTCCCCATGC
							410557	5-10-5	399	22211	22230	0	CAGTGGACACGGGTCCCCAT
410558	5-10-5	401	22213	22232	0	GGCAGTGGACACGGGTCCCC

Isis number	Motif	SEQ ID NO	5 target sites on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410559	5-10-5	403	22215	22234	0	GTGGCAGTGGACACGGGTCC
410560	5-10-5	404	22216	22235	0	GGTGGCAGTGGACACGGGTC
							410561	5-10-5	405	22217	22236	0	TGGTGGCAGTGGACACGGGT
410562	5-10-5	411	24096	24115	0	ACTTTGCATTCCAGACCTGG
							410563	5-10-5	413	24098	24117	0	TGACTTTGCATTCCAGACCT
410564	5-10-5	414	24099	24118	0	TTGACTTTGCATTCCAGACC
							410565	5-10-5	419	26112	26131	0	CAGATGGCAACGGCTGTCAC
410566	5-10-5	420	26113	26132	0	GCAGATGGCAACGGCTGTCA
							410567	5-10-5	421	26114	26133	0	AGCAGATGGCAACGGCTGTC
410568	5-10-5	422	26115	26134	0	CAGCAGATGGCAACGGCTGT
							410569	5-10-5	423	26116	26135	0	GCAGCAGATGGCAACGGCTG
410570	5-10-5	424	26118	26137	0	CGGCAGCAGATGGCAACGGC
							410571	5-10-5	425	26119	26138	0	CCGGCAGCAGATGGCAACGG
410572	5-10-5	427	26121	26140	0	CTCCGGCAGCAGATGGCAAC
							410573	5-10-5	428	26122	26141	0	GCTCCGGCAGCAGATGGCAA
410730	5-10-5	202	6594	6613	0	CGCCACTCATCTTCACCAGG
							410731	5-10-5	207	6604	6623	0	TCCAGCAGGTCGCCACTCAT
410732	5-10-5	214	9216	9235	0	GGGCTGGTATTCATCCGCCC
							410733	5-10-5	231	14942	14961	0	AAGTCGGTGACCATGACCCT
410734	5-10-5	279	18714	18733	0	CCGGCAGCGGTGACCAGCAC
							410735	5-10-5	291	19956	19975	0	TCCCCAGGGTCACCGGCTGG
410736	5-10-5	303	19992	20011	0	AGAGGTCCACACAGCGGCCA
							410737	5-10-5	313	20042	20061	0	GCAGGTGCTGCAGTCGCTGG
410738	5-10-5	324	20639	20658	0	GCTCGGCAGACAGCATCATG
							410739	5-10-5	336	20687	20706	0	CAGAGAAGTGGATCAGTCTC
410740	5-10-5	345	20715	20734	0	AACCAGGCCTCATTGATGAC
							410741	5-10-5	369	21129	21148	0	CCATCCGTGTAGGCCCCGAG
410742	5-10-5	159	2433	2452	0	GCCTGGAGCTGACGGTGCCC
							410743	5-10-5	170	2560	2579	0	TCCTCCTCGGAACGCAAGGC
410744	5-10-5	171	2585	2604	0	GTGCTCGGGTGCTTCGGCCA
							410745	5-10-5	172	2605	2624	0	TGGAAGGTGGCTGTGGTTCC
410746	5-10-5	176	6444	6463	0	CGTAGGTGCCAGGCAACCTC
							410747	5-10-5	177	6482	6501	0	TGACTGCGAGAGGTGGGTCT
410748	5-10-5	182	6528	6547	0	ATCCCCGGCGGGCAGCCTGG
							410749	5-10-5	197	6565	6584	0	AGAAGGCCATGGAAGACATG
410750	5-10-5	198	6575	6594	0	GAAGCCAGGAAGAAGGCCAT
							410752	5-10-5	209	9149	9168	0	GCAAAGACAGAGGAGTCCTC
410753	5-10-5	215	14877	14896	0	ATACACCTCCACCAGGCTGC
							410754	5-10-5	233	14954	14973	0	GGCACATTCTCGAAGTCGGT
410756	5-10-5	235	15254	15273	0	GGTGGGTGCCATGACTGTCA
							410757	5-10-5	240	15279	15298	0	TCCCGGCCGCTGACCACCCC
410758	5-10-5	256	15309	15328	0	CGCATGCTGGCACCCTTGGC
							410759	5-10-5	263	15358	15377	0	GGTGCCGCTAACCGTGCCCT
410761	5-10-5	271	18614	18633	0	GTGGCCCCACAGGCTGGACC
							410762	5-10-5	272	18627	18646	0	AGCAGCACCACCAGTGGCCC
410763	5-10-5	273	18649	18668	0	GCTGTACCCACCCGCCAGGG
							410764	5-10-5	274	18695	18714	0	CGACCCCAGCCCTCGCCAGG
410767	5-10-5	289	19941	19960	0	GCTGGTCTTGGGCATTGGTG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410768	5-10-5	305	20016	20035	0	CAATGATGTCCTCCCCTGGG
410769	5-10-5	318	20061	20080	0	TCCCACTCTGTGACACAAAG
							410770	5-10-5	327	20657	20676	0	CGGCCAGGGTGAGCTCCGGC
410771	5-10-5	360	20785	20804	0	ACCTGCCCCATGGGTGCTGG
							410772	5-10-5	364	21106	21125	0	GCTGACCATACAGTCCTGCA
410773	5-10-5	387	22189	22208	0	TGGCCTCAGCTGGTGGAGCT
							410774	5-10-5	406	22220	22239	0	TGTTGGTGGCAGTGGACACG
410776	5-10-5	408	23985	24004	0	GTGCCAAGGTCCTCCACCTC
							410777	5-10-5	409	24005	24024	0	TCAGCACAGGCGGCTTGTGG
410778	5-10-5	410	24035	24054	0	CCACGCACTGGTTGGGCTGA
							410779	5-10-5	416	24115	24134	0	CGGGATTCCATGCTCCTTGA
410781	5-10-5	418	25994	26013	0	GGAGGGCACTGCAGCCAGTC
							410782	5-10-5	429	26132	26151	0	CCAGGTGCCGGCTCCGGCAG
410783	5-10-5	430	26142	26161	0	GAGGCCTGCGCCAGGTGCCG

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:2 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 3-14-3 breach and widens motif in the table 6.Table 8 illustration the antisense compounds widened of the breach of target SEQ ID NO:2, it has the 3-14-3 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 8: the breach polymers antisense compounds of target SEQ ID NO:2 with 3-14-3 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399871	3-14-3	4	2274	2293	0	GCGCGGAATCCTGGCTGGGA
399872	3-14-3	5	2381	2400	0	GAGGAGACCTAGAGGCCGTG
							399873	3-14-3	6	2439	2458	0	AGGACCGCCTGGAGCTGACG
399874	3-14-3	7	2549	2568	0	ACGCAAGGCTAGCACCAGCT
							399875	3-14-3	9	2619	2638	0	CCTTGGCGCAGCGGTGGAAG
399876	3-14-3	10	6498	6517	0	GGCGGGCAGTGCGCTCTGAC
							399877	3-14-3	11	6537	6556	0	TGGTGAGGTATCCCCGGCGG
399878	3-14-3	14	6557	6576	0	ATGGAAGACATGCAGGATCT
							399879	3-14-3	15	6583	6602	0	TTCACCAGGAAGCCAGGAAG
399880	3-14-3	17	9130	9149	0	CCTCGATGTAGTCGACATGG
							399881	3-14-3	18	9210	9229	0	GTATTCATCCGCCCGGTACC
399882	3-14-3	19	14891	14910	0	CTGGTGTCTAGGAGATACAC
							399883	3-14-3	21	14916	14935	0	GATTTCCCGGTGGTCACTCT

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399884	3-14-3	24	14946	14965	0	CTCGAAGTCGGTGACCATGA
399885	3-14-3	25	14979	14998	0	GTGGAAGCGGGTCCCGTCCT
							399886	3-14-3	26	15264	15283	0	ACCCCTGCCAGGTGGGTGCC
399887	3-14-3	28	15298	15317	0	ACCCTTGGCCACGCCGGCAT
							399888	3-14-3	29	15334	15353	0	TTGGCAGTTGAGCACGCGCA
399890	3-14-3	32	18593	18612	0	GCTGGCTTTTCCGAATAAAC
							399891	3-14-3	33	18705	18724	0	GTGACCAGCACGACCCCAGC
399892	3-14-3	149	19933	19952	0	TGGGCATTGGTGGCCCCAAC
							399893	3-14-3	34	19962	19981	0	CCAAAGTCCCCAGGGTCACC
399894	3-14-3	128	19966	19985	0	GTCCCCAAAGTCCCCAGGGT
							399895	3-14-3	36	19976	19995	0	GCCAAAGTTGGTCCCCAAAG
399896	3-14-3	38	19997	20016	0	GGCAAAGAGGTCCACACAGC
							399897	3-14-3	39	20025	20044	0	TGGAGGCACCAATGATGTCC
399899	3-14-3	45	20691	20710	0	TTGGCAGAGAAGTGGATCAG
							399900	3-14-3	50	20726	20745	0	GGTCCTCAGGGAACCAGGCC
399901	3-14-3	87	20733	20752	0	ACCCGCTGGTCCTCAGGGAA
							399902	3-14-3	119	20762	20781	0	GCAGGGCGGCCACCAGGTTG
399904	3-14-3	54	21121	21140	0	GTAGGCCCCGAGTGTGCTGA
							399905	3-14-3	57	22096	22115	0	CGTTGTGGGCCCGGCAGACC
399906	3-14-3	58	22142	22161	0	AGCAGGCAGCACCTGGCAAT
							399907	3-14-3	59	22204	22223	0	CACGGGTCCCCATGCTGGCC
399908	3-14-3	60	24095	24114	0	CTTTGCATTCCAGACCTGGG
							399909	3-14-3	62	26117	26136	0	GGCAGCAGATGGCAACGGCT
399910	3-14-3	154	26217	26236	0	TTTTAAAGCTCAGCCCCAGC
							399911	3-14-3	64	26311	26330	0	TCAAGGGCCAGGCCAGCAGC
399912	3-14-3	66	26404	26423	0	ATGCCCCACAGTGAGGGAGG
							399913	3-14-3	67	26413	26432	0	AATGGTGAAATGCCCCACAG
399914	3-14-3	153	26456	26475	0	TTGGGAGCAGCTGGCAGCAC
							399915	3-14-3	68	26557	26576	0	CATGGGAAGAATCCTGCCTC
399916	3-14-3	69	26639	26658	0	GGAGATGAGGGCCATCAGCA
							399917	3-14-3	70	26707	26726	0	TAGATGCCATCCAGAAAGCT
399918	3-14-3	72	26790	26809	0	GGCATAGAGCAGAGTAAAGG
							399919	3-14-3	112	27034	27053	0	GAAGAGGCTTGGCTTCAGAG
399920	3-14-3	75	27244	27263	0	GCTCAAGGAGGGACAGTTGT
							399921	3-14-3	76	27279	27298	0	AAAGATAAATGTCTGCTTGC
399922	3-14-3	78	27350	27369	0	TCTTCAAGTTACAAAAGCAA
							399923	3-14-3	85	13681	13700	0	ACAAATTCCCAGACTCAGCA
399924	3-14-3	129	13816	13835	0	GTGCCATCTGAACAGCACCT
							399925	3-14-3	110	13926	13945	0	CCTGGAACCCCTGCAGCCAG
399926	3-14-3	152	13977	13996	0	TTCAGGCAGGTTGCTGCTAG
							399927	3-14-3	140	13998	14017	0	TCAGCCAGGCCAAAGGAAGA
399928	3-14-3	136	14122	14141	0	TAGGAGAAAGTAGGGAGAGC
							399929	3-14-3	132	14179	14198	0	TAAAAGCTGCAAGAGACTCA
399930	3-14-3	139	14267	14286	0	TCAGAGAAAACAGTCACCGA
							399931	3-14-3	142	14404	14423	0	TCATTTTAGAGACAGGAAGC
399932	3-14-3	113	14441	14460	0	GAATAACAGTGATGTCTGGC
							399933	3-14-3	138	14494	14513	0	TCACAGCTCACCGAGTCTGC
399934	3-14-3	98	14524	14543	0	AGTGTAAAATAAAGCCCCTA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399935	3-14-3	96	14601	14620	0	AGGACCCAAGTCATCCTGCT
399936	3-14-3	124	14631	14650	0	GGCCATCAGCTGGCAATGCT
							399937	3-14-3	133	14675	14694	0	TAGACAAGGAAAGGGAGGCC
399938	3-14-3	103	14681	14700	0	ATTTCATAGACAAGGAAAGG
							399939	3-14-3	155	14801	14820	0	CTTATAGTTAACACACAGAA
399943	3-14-3	102	5590	5609	0	ATGTGCAGAGATCAATCACA
							399944	3-14-3	127	10633	10652	0	GGTGGTAATTTGTCACAGCA
399945	3-14-3	84	11308	11327	0	AAGGTCACACAGTTAAGAGT
							399946	3-14-3	157	18561	18580	0	AGGAACAAAGCCAAGGTCAC
399947	3-14-3	126	22292	22311	0	GGTGCATAAGGAGAAAGAGA
							399948	3-14-3	147	24858	24877	0	TGAGTTCATTTAAGAGTGGA
399949	3-14-3	8	2556	2575	0	CCTCGGAACGCAAGGCTAGC
							399950	3-14-3	12	6543	6562	0	GGATCTTGGTGAGGTATCCC
399951	3-14-3	13	6552	6571	0	AGACATGCAGGATCTTGGTG
							399952	3-14-3	16	6588	6607	0	TCATCTTCACCAGGAAGCCA
399953	3-14-3	20	14896	14915	0	GTATGCTGGTGTCTAGGAGA
							399954	3-14-3	22	14922	14941	0	GCCCTCGATTTCCCGGTGGT
399955	3-14-3	23	14936	14955	0	GTGACCATGACCCTGCCCTC
							399956	3-14-3	27	15269	15288	0	TGACCACCCCTGCCAGGTGG
399957	3-14-3	30	15339	15358	0	TTCCCTTGGCAGTTGAGCAC
							399958	3-14-3	35	19971	19990	0	AGTTGGTCCCCAAAGTCCCC
399959	3-14-3	37	19988	20007	0	GTCCACACAGCGGCCAAAGT
							399960	3-14-3	40	20036	20055	0	GCTGCAGTCGCTGGAGGCAC
399961	3-14-3	41	20047	20066	0	ACAAAGCAGGTGCTGCAGTC
							399963	3-14-3	43	20635	20654	0	GGCAGACAGCATCATGGCTG
399964	3-14-3	44	20683	20702	0	GAAGTGGATCAGTCTCTGCC
							399965	3-14-3	46	20696	20715	0	CATCTTTGGCAGAGAAGTGG
399966	3-14-3	47	20702	20721	0	TGATGACATCTTTGGCAGAG
							399967	3-14-3	48	20709	20728	0	GCCTCATTGATGACATCTTT
399968	3-14-3	49	20721	20740	0	TCAGGGAACCAGGCCTCATT
							399969	3-14-3	51	20740	20759	0	GGTCAGTACCCGCTGGTCCT
399970	3-14-3	53	21091	21110	0	CTGCAAAACAGCTGCCAACC
							399971	3-14-3	55	21186	21205	0	AGAAACTGGAGCAGCTCAGC
399972	3-14-3	56	21192	21211	0	TCCTGGAGAAACTGGAGCAG
							399973	3-14-3	61	24100	24119	0	CTTGACTTTGCATTCCAGAC
399974	3-14-3	63	26222	26241	0	AACCATTTTAAAGCTCAGCC
							399975	3-14-3	65	26316	26335	0	CCCACTCAAGGGCCAGGCCA
399976	3-14-3	122	26389	26408	0	GGAGGGAGCTTCCTGGCACC
							399977	3-14-3	71	26713	26732	0	TCTGGCTAGATGCCATCCAG
399978	3-14-3	73	26795	26814	0	AGCCTGGCATAGAGCAGAGT
							399979	3-14-3	135	26801	26820	0	TAGCACAGCCTGGCATAGAG
399980	3-14-3	74	27040	27059	0	AAGTAAGAAGAGGCTTGGCT
							399981	3-14-3	77	27284	27303	0	ACCCAAAAGATAAATGTCTG
399982	3-14-3	99	27357	27376	0	ATAAATATCTTCAAGTTACA
							399983	3-14-3	100	13746	13765	0	ATCTCAGGACAGGTGAGCAA
399984	3-14-3	116	13760	13779	0	GAGTAGAGATTCTCATCTCA
							399985	3-14-3	117	13828	13847	0	GAGTCTTCTGAAGTGCCATC
399986	3-14-3	81	13903	13922	0	AAGCAGGGCCTCAGGTGGAA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							399987	3-14-3	83	13986	14005	0	AAGGAAGACTTCAGGCAGGT
399988	3-14-3	137	14112	14131	0	TAGGGAGAGCTCACAGATGC
							399989	3-14-3	92	14397	14416	0	AGAGACAGGAAGCTGCAGCT
399990	3-14-3	82	14670	14689	0	AAGGAAAGGGAGGCCTAGAG
							399991	3-14-3	156	14809	14828	0	AAGTCAACCTTATAGTTAAC
399993	3-14-3	107	3056	3075	0	CCCACTATAATGGCAAGCCC
							399994	3-14-3	80	4306	4325	0	AACCCAGTTCTAATGCACCT
399995	3-14-3	106	5140	5159	0	CCAGTCAGAGTAGAACAGAG
							399996	3-14-3	121	5599	5618	0	GGAGCCTACATGTGCAGAGA
399997	3-14-3	94	5667	5686	0	AGCATGGCACCAGCATCTGC
							399998	3-14-3	108	6652	6671	0	CCCAGCCCTATCAGGAAGTG
399999	3-14-3	144	7099	7118	0	TGACATCCAGGAGGGAGGAG
							400000	3-14-3	91	7556	7575	0	AGACTGATGGAAGGCATTGA
400001	3-14-3	131	7565	7584	0	GTGTTGAGCAGACTGATGGA
							400002	3-14-3	145	8836	8855	0	TGACATCTTGTCTGGGAGCC
400003	3-14-3	90	8948	8967	0	AGACTAGGAGCCTGAGTTTT
							400004	3-14-3	125	9099	9118	0	GGCCTGCAGAAGCCAGAGAG
400005	3-14-3	148	10252	10271	0	TGGCAGCAACTCAGACATAT
							400006	3-14-3	79	11472	11491	0	AAATGCAGGGCTAAAATCAC
400007	3-14-3	88	12715	12734	0	ACTGGATACATTGGCAGACA
							400008	3-14-3	111	12928	12947	0	CTAGAGGAACCACTAGATAT
400009	3-14-3	86	15471	15490	0	ACAGCATTCTTGGTTAGGAG
							400010	3-14-3	97	16134	16153	0	AGTCAAGCTGCTGCCCAGAG
400011	3-14-3	120	16668	16687	0	GCTAGTTATTAAGCACCTGC
							400012	3-14-3	150	17267	17286	0	TGTGAGCTCTGGCCCAGTGG
400013	3-14-3	115	18377	18396	0	GAGTAAGGCAGGTTACTCTC
							400014	3-14-3	134	18408	18427	0	TAGATGTGACTAACATTTAA
400015	3-14-3	105	19203	19222	0	CACATTAGCCTTGCTCAAGT
							400016	3-14-3	151	19913	19932	0	TGTGATGACCTGGAAAGGTG
400017	3-14-3	158	20100	20119	0	GTGGTGACTTACCAGCCACG
							400018	3-14-3	109	20188	20207	0	CCCCTGCACAGAGCCTGGCA
400019	3-14-3	141	20624	20643	0	TCATGGCTGCAATGCCTGGT
							400020	3-14-3	93	20995	21014	0	AGAGAGGAGGGCTTAAAGAA
400021	3-14-3	95	21082	21101	0	AGCTGCCAACCTGCAAAAAG
							400022	3-14-3	143	21481	21500	0	TGAAAATCCATCCAGCACTG
400023	3-14-3	89	21589	21608	0	AGAACCATGGAGCACCTGAG
							400024	3-14-3	123	21696	21715	0	GGCACTGCCCTTCCACCAAA
400025	3-14-3	118	24907	24926	0	GCACCATCCAGACCAGAATC
							400026	3-14-3	114	25413	25432	0	GAGAGGTTCAGATCCAGGCC
405604	3-14-3	236	15257	15276	0	CCAGGTGGGTGCCATGACTG
							405641	3-14-3	373	21183	21202	0	AACTGGAGCAGCTCAGCAGC
410574	3-14-3	184	6534	6553	0	TGAGGTATCCCCGGCGGGCA
							410575	3-14-3	185	6535	6554	0	GTGAGGTATCCCCGGCGGGC
410576	3-14-3	186	6536	6555	0	GGTGAGGTATCCCCGGCGGG
							410577	3-14-3	187	6538	6557	0	TTGGTGAGGTATCCCCGGCG
410578	3-14-3	188	6539	6558	0	CTTGGTGAGGTATCCCCGGC
							410579	3-14-3	189	6540	6559	0	TCTTGGTGAGGTATCCCCGG
410580	3-14-3	190	6541	6560	0	ATCTTGGTGAGGTATCCCCG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410581	3-14-3	191	6542	6561	0	GATCTTGGTGAGGTATCCCC
410582	3-14-3	192	6544	6563	0	AGGATCTTGGTGAGGTATCC
							410583	3-14-3	243	15291	15310	0	GCCACGCCGGCATCCCGGCC
410584	3-14-3	244	15292	15311	0	GGCCACGCCGGCATCCCGGC
							410585	3-14-3	245	15293	15312	0	TGGCC ACGCCGGCATCCCGG
410586	3-14-3	246	15294	15313	0	TTGGCCACGCCGGCATCCCG
							410587	3-14-3	247	15295	15314	0	CTTGGCCACGCCGGCATCCC
410588	3-14-3	248	15296	15315	0	CCTTGGCCACGCCGGCATCC
							410589	3-14-3	249	15297	15316	0	CCCTTGGCCACGCCGGCATC
410590	3-14-3	250	15299	15318	0	CACCCTTGGCCACGCCGGCA
							410591	3-14-3	251	15300	15319	0	GCACCCTTGGCCACGCCGGC
410592	3-14-3	252	15301	15320	0	GGCACCCTTGGCCACGCCGG
							410593	3-14-3	253	15302	15321	0	TGGCACCCTTGGCCACGCCG
410594	3-14-3	254	15303	15322	0	CTGGCACCCTTGGCCACGCC
							410595	3-14-3	255	15304	15323	0	GCTGGCACCCTTGGCCACGC
410596	3-14-3	348	20719	20738	0	AGGGAACCAGGCCTCATTGA
							410597	3-14-3	349	20720	20739	0	CAGGGAACCAGGCCTCATTG
410598	3-14-3	350	20722	20741	0	CTCAGGGAACCAGGCCTCAT
							410599	3-14-3	351	20723	20742	0	CCTCAGGGAACCAGGCCTCA
410600	3-14-3	352	20724	20743	0	TCCTCAGGGAACCAGGCCTC
							410601	3-14-3	353	20725	20744	0	GTCCTCAGGGAACCAGGCCT
410602	3-14-3	354	20727	20746	0	TGGTCCTCAGGGAACCAGGC
							410603	3-14-3	355	20728	20747	0	CTGGTCCTCAGGGAACCAGG
410604	3-14-3	356	20729	20748	0	GCTGGTCCTCAGGGAACCAG
							410605	3-14-3	376	22133	22152	0	CACCTGGCAATGGCGTAGAC
410606	3-14-3	377	22134	22153	0	GCACCTGGCAATGGCGTAGA
							410607	3-14-3	378	22135	22154	0	AGCACCTGGCAATGGCGTAG
410608	3-14-3	379	22136	22155	0	CAGCACCTGGCAATGGCGTA
							410609	3-14-3	380	22137	22156	0	GCAGCACCTGGCAATGGCGT
410610	3-14-3	381	22138	22157	0	GGCAGCACCTGGCAATGGCG
							410611	3-14-3	382	22139	22158	0	AGGCAGCACCTGGCAATGGC
410612	3-14-3	383	22140	22159	0	CAGGCAGCACCTGGCAATGG
							410613	3-14-3	384	22141	22160	0	GCAGGCAGCACCTGGCAATG
410614	3-14-3	385	22143	22162	0	TAGCAGGCAGCACCTGGCAA
							410615	3-14-3	388	22199	22218	0	GTCCCCATGCTGGCCTCAGC
410616	3-14-3	389	22200	22219	0	GGTCCCCATGCTGGCCTCAG
							410617	3-14-3	390	22201	22220	0	GGGTCCCCATGCTGGCCTCA
410618	3-14-3	391	22202	22221	0	CGGGTCCCCATGCTGGCCTC
							410619	3-14-3	392	22203	22222	0	ACGGGTCCCCATGCTGGCCT
410620	3-14-3	393	22205	22224	0	ACACGGGTCCCCATGCTGGC
							410621	3-14-3	394	22206	22225	0	GACACGGGTCCCCATGCTGG
410622	3-14-3	395	22207	22226	0	GGACACGGGTCCCCATGCTG
							410623	3-14-3	396	22208	22227	0	TGGACACGGGTCCCCATGCT
410624	3-14-3	397	22209	22228	0	GTGGACACGGGTCCCCATGC
							410625	3-14-3	398	22210	22229	0	AGTGGACACGGGTCCCCATG
410626	3-14-3	399	22211	22230	0	CAGTGGACACGGGTCCCCAT
							410627	3-14-3	400	22212	22231	0	GCAGTGGACACGGGTCCCCA
410628	3-14-3	401	22213	22232	0	GGCAGTGGACACGGGTCCCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410629	3-14-3	402	22214	22233	0	TGGCAGTGGACACGGGTCCC
410630	3-14-3	403	22215	22234	0	GTGGCAGTGGACACGGGTCC
							410631	3-14-3	404	22216	22235	0	GGTGGCAGTGGACACGGGTC
410632	3-14-3	405	22217	22236	0	TGGTGGCAGTGGACACGGGT
							410633	3-14-3	411	24096	24115	0	ACTTTGCATTCCAGACCTGG
410634	3-14-3	412	24097	24116	0	GACTTTGCATTCCAGACCTG
							410635	3-14-3	413	24098	24117	0	TGACTTTGCATTCCAGACCT
410636	3-14-3	414	24099	24118	0	TTGACTTTGCATTCCAGACC
							410637	3-14-3	419	26112	26131	0	CAGATGGCAACGGCTGTCAC
410638	3-14-3	420	26113	26132	0	GCAGATGGCAACGGCTGTCA
							410639	3-14-3	421	26114	26133	0	AGCAGATGGCAACGGCTGTC
410640	3-14-3	422	26115	26134	0	CAGCAGATGGCAACGGCTGT
							410641	3-14-3	423	26116	26135	0	GCAGCAGATGGCAACGGCTG
410642	3-14-3	424	26118	26137	0	CGGCAGCAGATGGCAACGGC
							410643	3-14-3	425	26119	26138	0	CCGGCAGCAGATGGCAACGG
410644	3-14-3	426	26120	26139	0	TCCGGCAGCAGATGGCAACG
							410645	3-14-3	427	26121	26140	0	CTCCGGCAGCAGATGGCAAC
410646	3-14-3	428	26122	26141	0	GCTCCGGCAGCAGATGGCAA

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:2 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 2-13-5 breach and widens motif in the table 6.Table 9 illustration the antisense compounds widened of the breach of target SEQ ID NO:2, it has the 2-13-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 9: the breach polymers antisense compounds of target SEQ ID NO:2 with 2-13-5 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410647	2-13-5	184	6534	6553	0	TGAGGTATCCCCGGCGGGCA
410648	2-13-5	185	6535	6554	0	GTGAGGTATCCCCGGCGGGC
							410649	2-13-5	186	6536	6555	0	GGTGAGGTATCCCCGGCGGG
410650	2-13-5	11	6537	6556	0	TGGTGAGGTATCCCCGGCGG
							410651	2-13-5	187	6538	6557	0	TTGGTGAGGTATCCCCGGCG
410652	2-13-5	188	6539	6558	0	CTTGGTGAGGTATCCCCGGC
							410653	2-13-5	189	6540	6559	0	TCTTGGTGAGGTATCCCCGG
410654	2-13-5	190	6541	6560	0	ATCTTGGTGAGGTATCCCCG
							410655	2-13-5	191	6542	6561	0	GATCTTGGTGAGGTATCCCC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410656	2-13-5	12	6543	6562	0	GGATCTTGGTGAGGTATCCC
410657	2-13-5	192	6544	6563	0	AGGATCTTGGTGAGGTATCC
							410658	2-13-5	243	15291	15310	0	GCCACGCCGGCATCCCGGCC
410659	2-13-5	244	15292	15311	0	GGCCACGCCGGCATCCCGGC
							410660	2-13-5	245	15293	15312	0	TGGCCACGCCGGCATCCCGG
410661	2-13-5	246	15294	15313	0	TTGGCCACGCCGGCATCCCG
							410662	2-13-5	247	15295	15314	0	CTTGGCCACGCCGGCATCCC
410663	2-13-5	248	15296	15315	0	CCTTGGCCACGCCGGCATCC
							410664	2-13-5	249	15297	15316	0	CCCTTGGCCACGCCGGCATC
410665	2-13-5	28	15298	15317	0	ACCCTTGGCCACGCCGGCAT
							410666	2-13-5	250	15299	15318	0	CACCCTTGGCCACGCCGGCA
410667	2-13-5	251	15300	15319	0	GCACCCTTGGCCACGCCGGC
							410668	2-13-5	252	15301	15320	0	GGCACCCTTGGCCACGCCGG
410669	2-13-5	253	15302	15321	0	TGGCACCCTTGGCCACGCCG
							410670	2-13-5	254	15303	15322	0	CTGGCACCCTTGGCCACGCC
410671	2-13-5	255	15304	15323	0	GCTGGCACCCTTGGCCACGC
							410672	2-13-5	348	20719	20738	0	AGGGAACCAGGCCTCATTGA
410673	2-13-5	349	20720	20739	0	CAGGGAACCAGGCCTCATTG
							410674	2-13-5	49	20721	20740	0	TCAGGGAACCAGGCCTCATT
410675	2-13-5	350	20722	20741	0	CTCAGGGAACCAGGCCTCAT
							410676	2-13-5	351	20723	20742	0	CCTCAGGGAACCAGGCCTCA
410677	2-13-5	352	20724	20743	0	TCCTCAGGGAACCAGGCCTC
							410678	2-13-5	353	20725	20744	0	GTCCTCAGGGAACCAGGCCT
410679	2-13-5	50	20726	20745	0	GGTCCTCAGGGAACCAGGCC
							410680	2-13-5	354	20727	20746	0	TGGTCCTCAGGGAACCAGGC
410681	2-13-5	355	20728	20747	0	CTGGTCCTCAGGGAACCAGG
							410682	2-13-5	356	20729	20748	0	GCTGGTCCTCAGGGAACCAG
410683	2-13-5	376	22133	22152	0	CACCTGGCAATGGCGTAGAC
							410684	2-13-5	377	22134	22153	0	GCACCTGGCAATGGCGTAGA
410685	2-13-5	378	22135	22154	0	AGCACCTGGCAATGGCGTAG
							410686	2-13-5	379	22136	22155	0	CAGCACCTGGCAATGGCGTA
410687	2-13-5	380	22137	22156	0	GCAGCACCTGGCAATGGCGT
							410688	2-13-5	381	22138	22157	0	GGCAGCACCTGGCAATGGCG
410689	2-13-5	382	22139	22158	0	AGGCAGCACCTGGCAATGGC
							410690	2-13-5	383	22140	22159	0	CAGGCAGCACCTGGCAATGG
410691	2-13-5	384	22141	22160	0	GCAGGCAGCACCTGGCAATG
							410692	2-13-5	58	22142	22161	0	AGCAGGCAGCACCTGGCAAT
410693	2-13-5	385	22143	22162	0	TAGCAGGCAGCACCTGGCAA
							410694	2-13-5	388	22199	22218	0	GTCCCCATGCTGGCCTCAGC
410695	2-13-5	389	22200	22219	0	GGTCCCCATGCTGGCCTCAG
							410696	2-13-5	390	22201	22220	0	GGGTCCCCATGCTGGCCTCA
410697	2-13-5	391	22202	22221	0	CGGGTCCCCATGCTGGCCTC
							410698	2-13-5	392	22203	22222	0	ACGGGTCCCCATGCTGGCCT
410699	2-13-5	59	22204	22223	0	CACGGGTCCCCATGCTGGCC
							410700	2-13-5	393	22205	22224	0	ACACGGGTCCCCATGCTGGC
410701	2-13-5	394	22206	22225	0	GACACGGGTCCCCATGCTGG
							410702	2-13-5	395	22207	22226	0	GGACACGGGTCCCCATGCTG
410703	2-13-5	396	22208	22227	0	TGGACACGGGTCCCCATGCT

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							410704	2-13-5	397	22209	22228	0	GTGGACACGGGTCCCCATGC
410705	2-13-5	398	22210	22229	0	AGTGGACACGGGTCCCCATG
							410706	2-13-5	399	22211	22230	0	CAGTGGACACGGGTCCCCAT
410707	2-13-5	400	22212	22231	0	GCAGTGGACACGGGTCCCCA
							410708	2-13-5	401	22213	22232	0	GGCAGTGGACACGGGTCCCC
410709	2-13-5	402	22214	22233	0	TGGCAGTGGACACGGGTCCC
							410710	2-13-5	403	22215	22234	0	GTGGCAGTGGACACGGGTCC
410711	2-13-5	404	22216	22235	0	GGTGGCAGTGGACACGGGTC
							410712	2-13-5	405	22217	22236	0	TGGTGGCAGTGGACACGGGT
410713	2-13-5	60	24095	24114	0	CTTTGCATTCCAGACCTGGG
							410714	2-13-5	411	24096	24115	0	ACTTTGCATTCCAGACCTGG
410715	2-13-5	412	24097	24116	0	GACTTTGCATTCCAGACCTG
							410716	2-13-5	413	24098	24117	0	TGACTTTGCATTCCAGACCT
410717	2-13-5	414	24099	24118	0	TTGACTTTGCATTCCAGACC
							410718	2-13-5	61	24100	24119	0	CTTGACTTTGCATTCCAGAC
410719	2-13-5	419	26112	26131	0	CAGATGGCAACGGCTGTCAC
							410720	2-13-5	420	26113	26132	0	GCAGATGGCAACGGCTGTCA
410721	2-13-5	421	26114	26133	0	AGCAGATGGCAACGGCTGTC
							410722	2-13-5	422	26115	26134	0	CAGCAGATGGCAACGGCTGT
410723	2-13-5	423	26116	26135	0	GCAGCAGATGGCAACGGCTG
							410724	2-13-5	62	26117	26136	0	GGCAGCAGATGGCAACGGCT
410725	2-13-5	424	26118	26137	0	CGGCAGCAGATGGCAACGGC
							410726	2-13-5	425	26119	26138	0	CCGGCAGCAGATGGCAACGG
410727	2-13-5	426	26120	26139	0	TCCGGCAGCAGATGGCAACG
							410728	2-13-5	427	26121	26140	0	CTCCGGCAGCAGATGGCAAC
410729	2-13-5	428	26122	26141	0	GCTCCGGCAGCAGATGGCAA

In certain embodiments, the antisense compounds target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:2 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 3-13-4 breach and widens motif in the table 6.Table 1O illustration the antisense compounds widened of the breach of target SEQ ID NO:2, it has the 3-13-4 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 10: the breach polymers antisense compounds of target SEQ ID NO:2 with 3-13-4 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Mispairing	Sequence (5 '-3 ')
							405526	3-13-4	236	15257	15276	0	CCAGGTGGGTGCCATGACTG
405557	3-13-4	50	20726	20745	0	GGTCCTCAGGGAACCAGGCC
							405564	3-13-4	373	21183	21202	0	AACTGGAGCAGCTCAGCAGC

Following embodiment has been listed the target region of PCSK9 nucleic acid.The example of also having showed the antisense compounds of these target regions of target.It is any to connecting or examine the modification of base between sugared module, nucleosides to should be appreciated that the sequence of listing among each SEQ ID NO is independent of.Therefore, can comprise independently connecting or examine one or more modifications of base between sugared module, nucleosides by the defined antisense compounds of SEQ ID NO.Represent to examine the combination of base sequence and motif by the antisense compounds of Isis numbering (Isis number) description.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, the following Nucleotide zone of the targeting compounds SEQ ID NO:2 of so shared at least one 8 Nucleotide core sequence:

2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667-5686,6444-6463,6482-6518,6492-6518,6528-6555,6528-6623,6534-6561,6535-6562,6536-6563,6537-6563,6538-6565,6539-6565,6540-6567,6541-6567,6542-6569,6546-6573,6557-6584,6575-6602,6585-6611,6594-6621,6596-6623,6652-6671,7099-7118,7556-7584,8836-8855,8948-8967,9099-9118,9099-9168,9130-9168,9207-9233,9207-9235,9209-9235,10252-10271,10633-10652,11308-11491,12715-12734,12928-12947,13681-13700,13746-13779,13816-13847,13903-13945,13977-14141,14179-14198,14267-14286,14397-14423,14441-14460,14494-14513,14494-14543,14524-14543,14601-14650,14670-14700,14675-14700,14801-14828,14877-14912,14877-14915,14877-14973,14916-14943,14916-14973,14925-14951,14934-14963,14946-14973,14979-14998,15254-15280,15254-15328,15264-15290,15279-15305,15291-15318,15292-15319,15293-15320,15294-15321,15294-15321,15295-15322,15296-15323,15297-15323,15298-15323,15299-15323,15300-15323,15301-15328,15330-15355,15330-15490,15339-15366,15358-15490,16134-16153,16668-16687,17267-17286,18377-18427,18561-18580,18591-18618,18591-18646,18591-18668,18695-18746,18705-18730,18709-18736,18719-18746,19203-20080,19931-19952,19954-19981,19964-19990,19973-19999,19982-20009,19992-20016,20016-20042,20025-20052,20036-20062,20045-20070,20100-20119,20188-20207,20624-20650,20624-20759,20629-20804,20633-20660,20635-20781,20643-20662,20657-20676,20670-20697,20680-20706,20683-20781,20689-20715,20698-20725,20709-20736,20717-20744,20718-20745,20719-20746,20720-20747,20721-20748,20722-20749,20727-20752,20735-20759,20762-21014,20785-21014,21082-21107,21082-21152,21091-21114,21118-21144,21127-21152,21181-21209,21181-21211,21183-21211,21481-21500,21589-21608,21692-21719,22000-22227,22096-22115,22096-22223,22096-22311,22133-22160,22133-22163,22134-22161,22135-22162,22136-22163,22137-22163,22138-22163,22189-22239,22199-22226,22199-22227,22200-22227,22201-22228,22202-22229,22203-22230,22204-22231,22205-22232,22206-22233,22207-22234,22208-22235,22209-22236,22210-22236,22210-22239,22211-22236,22212-22239,22292-22311,23985-24054,24035-24134,24095-24121,24858-24877,24907-24926,25413-25432,25994-26013,26112-26139,26112-26161,26112-27303,26113-26140,26114-26141,26115-26141,26116-26141,26117-26141,26117-26475,26118-26141,26120-26141,26132-26151,26142-26161,26217-26241,26311-26335,26389-26432,26456-26576,26635-26662,26707-26734,26707-26736,26790-26820,27034-27263,27279-27303 or 27350-27376.

In certain embodiments, target region is the Nucleotide 2274-2400 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2274-2400 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:4 or 5.In some such embodiment, the antisense compounds of the Nucleotide 2274-2400 of target SEQ ID NO:2 is selected from ISIS NO:395149,399871,395150 or 399872.

In certain embodiments, target region is the Nucleotide 2274-2575 of SEQ ID NO:2.In certain embodiments, the 2274-2575 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:4,5,6,7,8,159,160,162,163,164,165,166,167,168 or 169 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2274-2575 of target SEQ ID NO:2 is selected from ISISNO:395149,399871,395150,399872,410742,405999,395151,399873,405861,405862,405863,405864,395152,399874,405865,405866,405867,405868,399793 or 399949.

In certain embodiments, target region is the Nucleotide 2433-2570 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2433-2570 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:6,7,159,160,162,163,164,165,166 or 167 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2433-2570 of target SEQ ID NO:2 is selected from ISIS NO:395151,395152,399873,399874,405861,405862,405863,405864,405865,405866,405999 or 410742.

In certain embodiments, target region is the Nucleotide 2433-2579 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2433-2579 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:6,7,8,159,160,162,163,164,165,166,167,168,169 or 170 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2433-2579 of target SEQ ID NO:2 is selected from ISIS NO:395151,395152,399793,399873,399874,399949,405861,405862,405863,405864,405865,405866,405867,405868,405999,410742 or 410743.

In certain embodiments, target region is the Nucleotide 2549-2575 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2549-2575 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:7,8,166,167,168 or 169 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2549-2575 of target SEQ ID NO:2 is selected from ISIS NO:395152,399793,399874,399949,405865,405866,405867 or 405868.

In certain embodiments, target region is the Nucleotide 2552-2579 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2552-2579 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:8,168,169 or 170 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2552-2579 of target SEQ ID NO:2 is selected from ISIS NO:399793,399949,405867,405868 or 410743.

In certain embodiments, target region is the Nucleotide 2585-2638 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2585-2638 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:9,171 or 172 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2585-2638 of target SEQ ID NO:2 is selected from ISIS NO:395153,399875,410744 or 410745.

In certain embodiments, target region is the Nucleotide 2605-2638 of SEQ ID NO:2.In certain embodiments, the Nucleotide 2605-2638 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:8,168 or 169 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2605-2638 of target SEQ ID NO:2 is selected from ISIS NO:410745,395153 or 399875.

In certain embodiments, target region is the Nucleotide 3056-3075 of SEQ ID NO:2.In certain embodiments, the Nucleotide 3056-3075 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:107.In some such embodiment, the antisense compounds of the Nucleotide 3056-3075 of target SEQ ID NO:2 is selected from ISIS NO:399837 or 399993.

In certain embodiments, target region is the Nucleotide 4150-5159 of SEQ ID NO:2.In certain embodiments, the Nucleotide 4150-5159 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:106.In some such embodiment, the antisense compounds of the Nucleotide 4150-5159 of target SEQ ID NO:2 is selected from ISIS NO:399839 or 399995.

In certain embodiments, target region is the Nucleotide 4306-4325 of SEQ ID NO:2.In certain embodiments, the Nucleotide 4306-4325 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:80.In some such embodiment, the antisense compounds of the Nucleotide 4306-4325 of target SEQ ID NO:2 is selected from ISIS NO:399838 or 399994.

In certain embodiments, target region is the Nucleotide 5590-5618 of SEQ ID NO:2.In certain embodiments, the Nucleotide 5590-5618 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:102 or 121.In some such embodiment, the antisense compounds of the Nucleotide 5590-5618 of target SEQ ID NO:2 is selected from ISIS NO:395221,399840,399943 or 399996.

In certain embodiments, target region is the Nucleotide 5667-5686 of SEQ ID NO:2.In certain embodiments, the Nucleotide 5667-5686 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:94.In some such embodiment, the antisense compounds of the Nucleotide 5667-5686 of target SEQ ID NO:2 is selected from ISIS NO:399841 or 399997.

In certain embodiments, target region is the Nucleotide 6444-6463 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6444-6463 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:176.In some such embodiment, the antisense compounds of the Nucleotide 6444-6463 of target SEQ ID NO:2 is selected from ISIS NO:410746.

In certain embodiments, target region is the Nucleotide 6482-6518 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6482-6518 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:10,177,178,179,180 or 181 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6482-6518 of target SEQ ID NO:2 is selected from ISIS NO:395154,399876,406003,406004,406005,406006 or 410747.

In certain embodiments, target region is the Nucleotide 6492-6518 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6492-6518 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:10,178,179,180 or 181 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6492-6518 of target SEQ ID NO:2 is selected from ISIS NO:395154,399876,406003,406004,406005 or 406006.

In certain embodiments, target region is the Nucleotide 6528-6555 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6528-6555 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:182,183,184,185 or 186 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6528-6555 of target SEQ ID NO:2 is selected from ISIS NO:406007,410529,410530,410531,410574,410575,410576,410647,410648,410649 or 410748.

In certain embodiments, target region is the Nucleotide 6528-6623 of SEQ ID NO:2.In certain embodiments, the 6528-6623 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,13,13,14,15,16,182,183,184,185,186,187,188,189,190,191,192,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206 or 207 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6528-6623 of target SEQ ID NO:2 is selected from ISIS NO:395155,395156,395157,399794,399795,399796,399877,399878,399879,399950,399951,399952,406007,406008,406009,406010,406011,406012,406013,406014,406015,406016,406017,406018,406019,406020,410529,410530,410531,410532,410533,410534,410535,410574,410575,410576,410577,410578,410579,410580,410581,410582,410647,410648,410649,410650,410651,410652,410653,410654,410655,410656,410657,410730,410731,410748,410749, or 410750.

In certain embodiments, target region is the Nucleotide 6534-6561 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6534-6561 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,184,185,186,187,188,189,190 or 191 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6534-6561 of target SEQ ID NO:2 is selected from ISIS NO:395155,399877,406008,406009,410529,410530,410531,410532,410533,410534,410574,410575,410576,410577,410578,410579,410580,410581,410647,410648,410649,410650,410651,410652,410653,410654 or 410655.

In certain embodiments, target region is the Nucleotide 6535-6562 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6535-6562 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,185,186,187,188,189,190 or 191 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6535-6562 of target SEQ ID NO:2 is selected from ISIS NO:395155,399794,399877,399950,406008,406009,410530,410531,410532,410533,410534,410575,410576,410577,410578,410579,410580,410581,410648,410649,410650,410651,410652,410653,410654,410655 or 410656.

In certain embodiments, target region is the Nucleotide 6536-6563 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6536-6563 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,186,187,188,189,190,191 or 192 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6536-6563 of target SEQ ID NO:2 is selected from ISIS NO:395155,399794,399877,399950,406008,406009,410531,410532,410533,410534,410535,410576,410577,410578,410579,410580,410581,410582,410649,410650,410651,410652,410653,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6537-6563 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6537-6563 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:11,12,187,188,189,190,191 or 192 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6537-6563 of target SEQ ID NO:2 is selected from ISIS NO:395155,399794,399877,399950,406008,406009,410532,410533,410534,410535,410577,410578,410579,410580,410581,410582,410650,410651,410652,410653,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6538-6565 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6538-6565 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,187,188,189,190,191,192 or 193 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6538-6565 of target SEQ ID NO:2 is selected from ISIS NO:399794,399950,406008,406009,406010,410532,410533,410534,410535,410577,410578,410579,410580,410581,410582,410651,410652,410653,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6539-6565 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6539-6565 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,188,189,190,191,192 or 193 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6539-6565 of target SEQ IDNO:2 is selected from ISIS NO:399794,399950,406008,406009,406010,410533,410534,410535,410578,410579,410580,410581,410582,410652,410653,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6540-6567 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6540-6567 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,189,190,191,192,193 or 194 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6540-6567 of target SEQ IDNO:2 is selected from ISIS NO:399794,399950,406009,406010,406011,410533,410534,410535,410579,410580,410581,410582,410653,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6541-6567 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6541-6567 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,190,191,192,193 or 194 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6541-6567 of target SEQ ID NO:2 is selected from ISIS NO:399794,399950,406009,406010,406011,410534,410535,410580,410581,410582,410654,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6542-6569 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6542-6569 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:12,191,192,193,194 or 195 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6542-6569 of target SEQ ID NO:2 is selected from ISIS NO:399794,399950,406010,406011,406012,410534,410535,410581,410582,410655,410656 or 410657.

In certain embodiments, target region is the Nucleotide 6546-6573 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6546-6573 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:13,193,194,195 or 196 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6546-6573 of target SEQ ID NO:2 is selected from ISIS NO:399795,399951,406010,406011,406012 or 406013.

In certain embodiments, target region is the Nucleotide 6557-6584 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6557-6584 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:14,197 or 198 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6557-6584 of target SEQ ID NO:2 is selected from ISIS NO:395156,399878,410749 or 410750.

In certain embodiments, target region is the Nucleotide 6575-6602 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6575-6602 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:15 or 198.In some such embodiment, the antisense compounds of the Nucleotide 6575-6602 of target SEQ ID NO:2 is selected from ISIS NO:395157,399879 or 410750.

In certain embodiments, target region is the Nucleotide 6585-6611 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6585-6611 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:16,199,200 or 201 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6585-6611 of target SEQ ID NO:2 is selected from ISIS NO:399796,399952,406014,406015 or 406016.

In certain embodiments, target region is the Nucleotide 6594-6621 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6594-6621 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:202,203,204,205 or 206 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6594-6621 of target SEQ ID NO:2 is selected from ISIS NO:406017,406018,406019,406020 or 410730.

In certain embodiments, target region is the Nucleotide 6596-6623 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6596-6623 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:203,204,205,206 or 207 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 6596-6623 of target SEQ ID NO:2 is selected from ISIS NO:406017,406018,406019,406020 or 410731.

In certain embodiments, target region is the Nucleotide 6652-6671 of SEQ ID NO:2.In certain embodiments, the Nucleotide 6652-6671 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:108.In some such embodiment, the antisense compounds of the Nucleotide 6652-6671 of target SEQ ID NO:2 is selected from ISIS NO:399842 or 399998.

In certain embodiments, target region is the Nucleotide 7099-7118 of SEQ ID NO:2.In certain embodiments, the Nucleotide 7099-7118 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:114.In some such embodiment, the antisense compounds of the Nucleotide 7099-7118 of target SEQ ID NO:2 is selected from ISIS NO:399843 or 399999.

In certain embodiments, target region is the Nucleotide 7556-7584 of SEQ ID NO:2.In certain embodiments, the Nucleotide 7556-7584 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:91 or 131.In some such embodiment, the antisense compounds of the Nucleotide 7556-7584 of target SEQ ID NO:2 is selected from ISIS NO:399844,399845,400000 or 400001.

In certain embodiments, target region is the Nucleotide 8836-8855 of SEQ ID NO:2.In certain embodiments, the Nucleotide 8836-8855 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:145.In some such embodiment, the antisense compounds of the Nucleotide 8836-8855 of target SEQ ID NO:2 is selected from ISIS NO:399846 or 400002.

In certain embodiments, target region is the Nucleotide 8948-8967 of SEQ ID NO:2.In certain embodiments, the Nucleotide 8948-8967 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:90.In some such embodiment, the antisense compounds of the Nucleotide 8948-8967 of target SEQ ID NO:2 is selected from ISIS NO:399847 or 400003.

In certain embodiments, target region is the Nucleotide 9099-9118 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9099-9118 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:125.In some such embodiment, the antisense compounds of the Nucleotide 9099-9118 of target SEQ ID NO:2 is selected from ISIS NO:399848 or 400004.

In certain embodiments, target region is the Nucleotide 9099-9168 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9099-9168 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:17,125 or 209 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 9099-9168 of target SEQ ID NO:2 is selected from ISIS NO:395158,399848,399880,400004 or 410752.

In certain embodiments, target region is the Nucleotide 9130-9168 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9130-9168 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:17.In some such embodiment, the antisense compounds of the Nucleotide 9130-9168 of target SEQ ID NO:2 is selected from ISIS NO:395158 or 399880.

In certain embodiments, target region is the Nucleotide 9207-9233 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9207-9233 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:18,210,211,212 or 213 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 9207-9233 of target SEQ ID NO:2 is selected from ISIS NO:395159,399881,406021,406022,406023 or 406024.

In certain embodiments, target region is the Nucleotide 9207-9235 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9207-9235 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:18,210,211,212,213 or 214 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 9207-9235 of target SEQ ID NO:2 is selected from ISIS NO:395159,399881,406021,406022,406023,406024 or 410732.

In certain embodiments, target region is the Nucleotide 9209-9235 of SEQ ID NO:2.In certain embodiments, the Nucleotide 9209-9235 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:18,211,212,213 or 214 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 9209-9235 of target SEQ ID NO:2 is selected from ISIS NO:395159,399881,406022,406023,406024 or 410732.

In certain embodiments, target region is the Nucleotide 10252-10271 of SEQ ID NO:2.In certain embodiments, the Nucleotide 10252-10271 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:148.In some such embodiment, the antisense compounds of the Nucleotide 10252-10271 of target SEQ ID NO:2 is selected from ISIS NO:399849 or 400005.

In certain embodiments, target region is the Nucleotide 10633-10652 of SEQ ID NO:2.In certain embodiments, the Nucleotide 10633-10652 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:127.In some such embodiment, the antisense compounds of the Nucleotide 10633-10652 of target SEQ ID NO:2 is selected from ISIS NO:395222 or 399944.

In certain embodiments, target region is the Nucleotide 11308-11491 of SEQ ID NO:2.In certain embodiments, the Nucleotide 11308-11491 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:79 or 84.In some such embodiment, the antisense compounds of the Nucleotide 11308-11491 of target SEQ ID NO:2 is selected from ISIS NO:395223,399850,399945 or 400006.

In certain embodiments, target region is the Nucleotide 12715-12734 of SEQ ID NO:2.In certain embodiments, the Nucleotide 12715-12734 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:88.In some such embodiment, the antisense compounds of the Nucleotide 12715-12734 of target SEQ ID NO:2 is selected from ISIS NO:399851 or 400007.

In certain embodiments, target region is the Nucleotide 12928-12947 of SEQ ID NO:2.In certain embodiments, the Nucleotide 12928-12947 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:111.In some such embodiment, the antisense compounds of the Nucleotide 12928-12947 of target SEQ ID NO:2 is selected from ISIS NO:399852 or 400008.

In certain embodiments, target region is the Nucleotide 13681-13700 of SEQ ID NO:2.In certain embodiments, the Nucleotide 13681-13700 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:85.In some such embodiment, the antisense compounds of the Nucleotide 13681-13700 of target SEQ ID NO:2 is selected from ISIS NO:395201 or 399923.

In certain embodiments, target region is the Nucleotide 13746-13779 of SEQ ID NO:2.In certain embodiments, the Nucleotide 13746-13779 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:100 or 116.In some such embodiment, the antisense compounds of the Nucleotide 13746-13779 of target SEQ ID NO:2 is selected from ISIS NO:399827,399828,399983 or 399984.

In certain embodiments, target region is the Nucleotide 13816-13847 of SEQ ID NO:2.In certain embodiments, the Nucleotide 13816-13847 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:117 or 129.In some such embodiment, the antisense compounds of the Nucleotide 13816-13847 of target SEQ ID NO:2 is selected from ISIS NO:395202,399829,399924 or 399985.

In certain embodiments, target region is the Nucleotide 13903-13945 of SEQ ID NO:2.In certain embodiments, the Nucleotide 13903-13945 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:81 or 110.In some such embodiment, the antisense compounds of the Nucleotide 13903-13945 of target SEQ ID NO:2 is selected from ISIS NO:395203,399830,399925 or 399986.

In certain embodiments, target region is the Nucleotide 13977-14141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 13977-14141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:83,136,137,140 or 152 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 13977-14141 of target SEQ ID NO:2 is selected from ISIS NO:395204,395205,395206,399831,399832,399926,399927,399928,399987 or 399988.

In certain embodiments, target region is the Nucleotide 14179-14198 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14179-14198 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:132.In some such embodiment, the antisense compounds of the Nucleotide 14179-14198 of target SEQ ID NO:2 is selected from ISIS NO:395207 or 399929.

In certain embodiments, target region is the Nucleotide 14267-14286 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14267-14286 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:139.In some such embodiment, the antisense compounds of the Nucleotide 14267-14286 of target SEQ ID NO:2 is selected from ISIS NO:395208 or 399930.

In certain embodiments, target region is the Nucleotide 14397-14423 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14397-14423 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:92 or 142.In some such embodiment, the antisense compounds of the Nucleotide 14397-14423 of target SEQ ID NO:2 is selected from ISIS NO:395209,399833,399931 or 399989.

In certain embodiments, target region is the Nucleotide 14441-14460 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14441-14460 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:113.In some such embodiment, the antisense compounds of the Nucleotide 14441-14460 of target SEQ ID NO:2 is selected from ISIS NO:395210 or 399932.

In certain embodiments, target region is the Nucleotide 14494-14513 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14494-14513 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:138.In some such embodiment, the antisense compounds of the Nucleotide 14494-14513 of target SEQ ID NO:2 is selected from ISIS NO:395211 or 399933.

In certain embodiments, target region is the Nucleotide 14494-14543 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14494-14543 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:98 or 138.In some such embodiment, the antisense compounds of the Nucleotide 14494-14543 of target SEQ ID NO:2 is selected from ISIS NO:395211,395212,399933 or 399934.

In certain embodiments, target region is the Nucleotide 14524-14543 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14524-14543 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:98.In some such embodiment, the antisense compounds of the Nucleotide 14524-14543 of target SEQ ID NO:2 is selected from ISIS NO:395212 or 399934.

In certain embodiments, target region is the Nucleotide 14601-14650 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14601-14650 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:96 or 124.In some such embodiment, the antisense compounds of the Nucleotide 14601-14650 of target SEQ ID NO:2 is selected from ISIS NO:395213,395214,399935 or 399936.

In certain embodiments, target region is the Nucleotide 14670-14700 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14670-14700 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:82,103 or 133 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14670-14700 of target SEQ ID NO:2 is selected from ISIS NO:395215,395216,399834,399937,399938 or 399990.

In certain embodiments, target region is the Nucleotide 14675-14700 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14675-14700 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:103 or 133.In some such embodiment, the antisense compounds of the Nucleotide 14675-14700 of target SEQ ID NO:2 is selected from ISIS NO:395215,395216,399937 or 399938.

In certain embodiments, target region is the Nucleotide 14801-14828 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14801-14828 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:155 or 156.In some such embodiment, the antisense compounds of the Nucleotide 14801-14828 of target SEQ ID NO:2 is selected from ISIS NO:395217,399835,399939 or 399991.

In certain embodiments, target region is the Nucleotide 14877-14912 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14877-14912 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,215,216 or 217 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14877-14912 of target SEQ ID NO:2 is selected from ISIS NO:395160,399882,406025,406026 or 410753.

In certain embodiments, target region is the Nucleotide 14877-14915 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14877-14915 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,215,216 or 217 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14877-14915 of target SEQ ID NO:2 is selected from ISIS NO:395160,399797,399882,399953,406025,406026 or 410753.

In certain embodiments, target region is the Nucleotide 14877-14973 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14877-14973 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,21,22,23,24,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232 or 233 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14877-14973 of target SEQ ID NO:2 is selected from ISISNO:395160,395161,395162,399797,399798,399799,399882,399883,399884,399953,399954,399955,405869,405870,405871,405872,405873,405874,405875,405876,406025,406026,406027,406028,406029,406030,406031,406032,410733,410753 or 410754.

In certain embodiments, target region is the Nucleotide 14916-14943 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14916-14943 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,218,219,220,221,222 or 223 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14916-14943 of target SEQ ID NO:2 is selected from ISIS NO:395161,399798,399883,399954,405869,405870,405871,405872,405873 or 405874.

In certain embodiments, target region is the Nucleotide 14916-14973 of SEQ ID NO:2.In certain embodiments, the 14916-14973 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,24,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232 or 223 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14916-14973 of target SEQ ID NO:2 is selected from ISIS NO:395161,395162,399798,399799,399883,399884,399954,399955,405869,405870,405871,405872,405873,405874,405875,405876,406027,406028,406029,406030,406031,406032,410733 or 410754.

In certain embodiments, target region is the Nucleotide 14925-14951 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14925-14951 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:224,225,226 or 227 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14925-14951 of target SEQ ID NO:2 is selected from ISIS NO:405875,405876,406027 or 406028.

In certain embodiments, target region is the Nucleotide 14934-14963 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14934-14963 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:23,228,229,230,231 or 232 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 14934-14963 of target SEQ IDNO:2 is selected from ISIS NO:399799,399955,406029,406030,406031,406032 or 410733.

In certain embodiments, target region is the Nucleotide 14946-14973 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14946-14973 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:24 or 233.In some such embodiment, the antisense compounds of the Nucleotide 14946-14973 of target SEQ ID NO:2 is selected from ISIS NO:395162,399884 or 410754.

In certain embodiments, target region is the Nucleotide 14979-14998 of SEQ ID NO:2.In certain embodiments, the Nucleotide 14979-14998 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:25.In some such embodiment, the antisense compounds of the Nucleotide 14979-14998 of target SEQ ID NO:2 is selected from ISIS NO:395163 or 399885.

In certain embodiments, target region is the Nucleotide 15254-15280 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15254-15280 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:235,236 or 237 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15254-15280 of target SEQ ID NO:2 is selected from ISIS NO:405526,405604,406033 or 410756.

In certain embodiments, target region is the Nucleotide 15254-15328 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15254-15328 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,28,235,236,237,238,239,240,241,242,243,243,243,244,245,246,247,248,249,250,251,252,253,254,255,256 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15254-15328 of target SEQ ID NO:2 is selected from ISIS NO:395164,395165,399800,399886,399887,399956,405526,405604,405877,405878,405879,405880,405881,405882,405883,405884,406033,406034,406035,406036,406037,406038,409126,410536,410537,410538,410539,410583,410584,410585,410586,410587,410588,410589,410590,410591,410592,410593,410594,410595,410658,410659,410660,410661,410662,410663,410664,410665,410666,410667,410668,410669,410670,410671,410756,410757, or 410758.

In certain embodiments, target region is the Nucleotide 15264-15290 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15264-15290 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,27,238 or 239 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15264-15290 of target SEQ ID NO:2 is selected from ISIS NO:395164,399800,399886,399956,406034 or 406035.

In certain embodiments, target region is the Nucleotide 15279-15305 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15279-15305 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:240,241 or 242 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15279-15305 of target SEQ ID NO:2 is selected from ISIS NO:406036,406037 or 410757.

In certain embodiments, target region is the Nucleotide 15291-15318 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15291-15318 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,243,244,245,246,247,248,249,250 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15291-15318 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405877,405878,405879,405880,405881,406038,409126,410536,410537,410583,410584,410585,410586,410587,410588,410589,410590,410658,410659,410660,410661,410662,410663,410664,410665 or 410666.

In certain embodiments, target region is the Nucleotide 15292-15319 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15292-15319 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,244,245,246,247,248,249,250 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15292-15319 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405877,405878,405879,405880,405881,406038,409126,410537,410584,410585,410586,410587,410588,410589,410590,410659,410660,410661,410662,410663,410664,410665 or 410666.

In certain embodiments, target region is the Nucleotide 15293-15320 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15293-15320 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,245,246,247,248,249,250,251,252 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15293-15320 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405877,405878,405879,405880,405881,405882,405883,406038,409126,410585,410586,410587,410588,410589,410590,410591,410592,410660,410661,410662,410663,410664,410665,410666,410667 or 410668.

In certain embodiments, target region is the Nucleotide 15294-15321 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15294-15321 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,246,247,248,249,250,251,252,253 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15294-15321 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405877,405878,405879,405880,405881,405882,405883,405884,409126,410586,410587,410588,410589,410590,410591,410592,410593,410661,410662,410663,410664,410665,410666,410667,410668 or 410669.

In certain embodiments, target region is the Nucleotide 15294-15321 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15294-15321 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,246,247,248,249,250,251,252,253 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15294-15321 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405877,405878,405879,405880,405881,405882,405883,405884,409126,410586,410587,410588,410589,410590,410591,410592,410593,410661,410662,410663,410664,410665,410666,410667,410668 or 410669.

In certain embodiments, target region is the Nucleotide 15295-15322 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15295-15322 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,247,248,249,250,250,251,252,253,254 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15295-15322 of target SEQ ID NO:2 is selected from ISIS NO:395165,399887,405878,405879,405880,405881,405882,405883,405884,409126,410538,410587,410588,410589,410590,410591,410592,410593,410594,410662,410663,410664,410665,410666,410667,410668,410669 or 410670.

In certain embodiments, target region is the Nucleotide 15296-15323 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15296-15323 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,248,249,250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15296-15323 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405879,405880,405881,405882,405883,405884,409126,410538,410539,410588,410589,410590,410591,410592,410593,410594,410595,410663,410664,410665,410666,410667,410668,410669,410670 or 410671.

In certain embodiments, target region is the Nucleotide 15297-15323 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15297-15323 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,249,250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15297-15323 of target SEQ ID NO:2 is selected from ISISNO:395165,399887,405880,405881,405882,405883,405884,409126,410538,410539,410589,410590,410591,410592,410593,410594,410595,410664,410665,410666,410667,410668,410669,410670 or 410671.

In certain embodiments, target region is the Nucleotide 15298-15323 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15298-15323 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15298-15323 of target SEQ ID NO:2 is selected from ISIS NO:395165,399887,405881,405882,405883,405884,409126,410538,410539,410590,410591,410592,410593,410594,410595,410665,410666,410667,410668,410669,410670 or 410671.

In certain embodiments, target region is the Nucleotide 15299-15323 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15299-15323 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:250,251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15299-15323 of target SEQ IDNO:2 is selected from ISIS NO:405881,405882,405883,405884,410538,410539,410590,410591,410592,410593,410594,410595,410666,410667,410668,410669,410670 or 410671.

In certain embodiments, target region is the Nucleotide 15300-15323 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15300-15323 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15300-15323 of target SEQ ID NO:2 is selected from ISIS NO:405882,405883,405884,410538,410539,410591,410592,410593,410594,410595,410667,410668,410669,410670 or 410671.

In certain embodiments, target region is the Nucleotide 15301-15328 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15301-15328 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:252,253,254,255 or 256 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15301-15328 of target SEQ ID NO:2 is selected from ISIS NO:405883,405884,410538,410539,410592,410593,410594,410595,410668,410669,410670,410671 or 410758.

In certain embodiments, target region is the Nucleotide 15330-15355 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15330-15355 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:29,257,258 or 259 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15330-15355 of target SEQ ID NO:2 is selected from ISIS NO:395166,399888,406039,406040 or 406041.

In certain embodiments, target region is the Nucleotide 15330-15490 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15330-15490 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:29,30,86,257,258,259,260,261,262 or 263 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15330-15490 of target SEQ ID NO:2 is selected from ISISNO:395166,399801,399853,399888,399957,400009,406039,406040,406041,406042,406043,406044 or 410759.

In certain embodiments, target region is the Nucleotide 15339-15366 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15339-15366 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:30,260,261 or 262 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 15339-15366 of target SEQ ID NO:2 is selected from ISIS NO:399801,399957,406042,406043 or 406044.

In certain embodiments, target region is the Nucleotide 15358-15490 of SEQ ID NO:2.In certain embodiments, the Nucleotide 15358-15490 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:86 or 263.In some such embodiment, the antisense compounds of the Nucleotide 15358-15490 of target SEQ ID NO:2 is selected from ISIS NO:399853,400009 or 410759.

In certain embodiments, target region is the Nucleotide 16134-16153 of SEQ ID NO:2.In certain embodiments, the Nucleotide 16134-16153 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:97.In some such embodiment, the antisense compounds of the Nucleotide 16134-16153 of target SEQ ID NO:2 is selected from ISIS NO:399854 or 400010.

In certain embodiments, target region is the Nucleotide 16668-16687 of SEQ ID NO:2.In certain embodiments, the Nucleotide 16668-16687 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:120.In some such embodiment, the antisense compounds of the Nucleotide 16668-16687 of target SEQ ID NO:2 is selected from ISIS NO:399855 or 400011.

In certain embodiments, target region is the Nucleotide 17267-17286 of SEQ ID NO:2.In certain embodiments, the Nucleotide 17267-17286 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:150.In some such embodiment, the antisense compounds of the Nucleotide 17267-17286 of target SEQ ID NO:2 is selected from ISIS NO:399856 or 400012.

In certain embodiments, target region is the Nucleotide 18377-18427 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18377-18427 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:115 or 134.In some such embodiment, the antisense compounds of the Nucleotide 18377-18427 of target SEQ ID NO:2 is selected from ISIS NO:399857,399858,400013 or 400014.

In certain embodiments, target region is the Nucleotide 18561-18580 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18561-18580 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:157.In some such embodiment, the antisense compounds of the Nucleotide 18561-18580 of target SEQ ID NO:2 is selected from ISIS NO:395224 or 399946.

In certain embodiments, target region is the Nucleotide 18591-18618 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18591-18618 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:32,266,267,268 or 269 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18591-18618 of target SEQ ID NO:2 is selected from ISIS NO:395168,399890,405909,405910,405911 or 406045.

In certain embodiments, target region is the Nucleotide 18591-18646 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18591-18646 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:32,32,266,267,268,269,270,271 or 272 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18591-18646 of target SEQ ID NO:2 is selected from ISIS NO:395168,399890,405909,405910,405911,405912,406045,410761 or 410762.

In certain embodiments, target region is the Nucleotide 18591-18668 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18591-18668 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:32,266,267,268,269,270,271,272 or 273 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18591-18668 of target SEQ ID NO:2 is selected from ISISNO:395168,399890,405909,405910,405911,405912,406045,410761,410762 or 410763.

In certain embodiments, target region is the Nucleotide 18695-18746 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18695-18746 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,274,275,276,277,278,279,280,281,282,283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18695-18746 of target SEQ ID NO:2 is selected from ISIS NO:395169,399891,405913,405914,405915,405916,405917,405918,405919,405920,405921,405922,410734 or 410764.

In certain embodiments, target region is the Nucleotide 18705-18730 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18705-18730 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,275,276 or 277 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18705-18730 of target SEQ ID NO:2 is selected from ISIS NO:395169,399891,405913,405914 or 405915.

In certain embodiments, target region is the Nucleotide 18709-18736 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18709-18736 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:276,277,278,279 or 280 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18709-18736 of target SEQ ID NO:2 is selected from ISIS NO:405914,405915,405916,405917 or 410734.

In certain embodiments, target region is the Nucleotide 18719-18746 of SEQ ID NO:2.In certain embodiments, the Nucleotide 18719-18746 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:281,282,283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 18719-18746 of target SEQ ID NO:2 is selected from ISIS NO:405918,405919,405920,405921 or 405922.

In certain embodiments, target region is the Nucleotide 19203-20080 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19203-20080 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:34,35,36,37,38,39,40,41,105,128,149,151,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317 or 318 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19203-20080 of target SEQ ID NO:2 is selected from ISIS NO:395170,395171,395172,395173,395174,395175,399802,399803,399804,399805,399859,399860,399892,399893,399894,399895,399896,399897,399958,399959,399960,399961,400015,400016,405923,405924,405925,405926,405927,405928,405929,405930,405931,405932,405933,405934,405935,405936,405937,405938,405939,405940,405941,405942,405943,405944,405945,405946,405947,410735,410736,410737,410767,410768 or 410769.

In certain embodiments, target region is the Nucleotide 19931-19952 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19931-19952 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:149 or 188.In some such embodiment, the antisense compounds of the Nucleotide 19931-19952 of target SEQ ID NO:2 is selected from ISIS NO:395170,399892 or 405923.

In certain embodiments, target region is the Nucleotide 19954-19981 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19954-19981 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:34,290,291,292 or 293 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19954-19981 of target SEQ ID NO:2 is selected from ISIS NO:395171,399893,405924,405925,405926 or 410735.

In certain embodiments, target region is the Nucleotide 19964-19990 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19964-19990 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:35,128,128,294 or 295 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19964-19990 of target SEQ ID NO:2 is selected from ISIS NO:395172,399802,399894,399958,405927 or 405928.

In certain embodiments, target region is the Nucleotide 19973-19999 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19973-19999 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:36,296,297 or 298 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19973-19999 of target SEQ ID NO:2 is selected from ISIS NO:395173,399895,405929,405930 or 405931.

In certain embodiments, target region is the Nucleotide 19982-20009 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19982-20009 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:37,299,300,301 or 302 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19982-20009 of target SEQ ID NO:2 is selected from ISIS NO:399803,399959,405932,405933,405934 or 405935.

In certain embodiments, target region is the Nucleotide 19992-20016 of SEQ ID NO:2.In certain embodiments, the Nucleotide 19992-20016 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:38,303 or 304 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 19992-20016 of target SEQ ID NO:2 is selected from ISIS NO:395174,399896,405936 or 410736.

In certain embodiments, target region is the Nucleotide 20016-20042 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20016-20042 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:305 or 306.In some such embodiment, the antisense compounds of the Nucleotide 20016-20042 of target SEQ ID NO:2 is selected from ISIS NO:405937 or 410768.

In certain embodiments, target region is the Nucleotide 20025-20052 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20025-20052 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:39,307,308,309 or 310 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20025-20052 of target SEQ ID NO:2 is selected from ISIS NO:395175,399897,405938,405939,405940 or 405941.

In certain embodiments, target region is the Nucleotide 20036-20062 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20036-20062 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:40,311,312,313 or 314 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20036-20062 of target SEQ ID NO:2 is selected from ISIS NO:399804,399960,405942,405943,405944 or 410737.

In certain embodiments, target region is the Nucleotide 20045-20070 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20045-20070 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:41,315,316 or 317 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20045-20070 of target SEQ ID NO:2 is selected from ISIS NO:399805,399961,405945,405946 or 405947.

In certain embodiments, target region is the Nucleotide 20100-20119 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20100-20119 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:158.In some such embodiment, the antisense compounds of the Nucleotide 20100-20119 of target SEQ ID NO:2 is selected from ISIS NO:399861 or 400017.

In certain embodiments, target region is the Nucleotide 20188-20207 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20188-20207 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:109.In some such embodiment, the antisense compounds of the Nucleotide 20188-20207 of target SEQ ID NO:2 is selected from ISIS NO:399862 or 400018.

In certain embodiments, target region is the Nucleotide 20624-20650 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20624-20650 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:141,320 or 321 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20624-20650 of target SEQ ID NO:2 is selected from ISIS NO:399863,400019,405949 or 405950.

In certain embodiments, target region is the Nucleotide 20624-20759 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20624-20759 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,44,45,46,47,48,49,50,51,87,141,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20624-20759 of target SEQ ID NO:2 is selected from ISISNO:395177,395178,395179,399807,399808,399809,399810,399811,399812,399813,399863,399899,399900,399901,399963,399964,399965,399966,399967,399968,399969,400019,405557,405885,405886,405887,405888,405889,405890,405891,405892,405949,405950,405951,405952,405953,405954,405955,405956,405957,405958,405959,405960,405961,405962,405963,405964,405965,405966,405967,405968,405969,405970,405971,405972,405973,405974,408653,410540,410596,410597,410598,410599,410600,410601,410602,410603,410604,410672,410673,410674,410675,410676,410677,410678,410679,410680,410681,410682,410738,410739,410740 or 410770.

In certain embodiments, target region is the Nucleotide 20629-20804 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20629-20804 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,44,45,46,47,48,49,50,51,87,119,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,356,357,358,359 or 360 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20629-20804 of target SEQ ID NO:2 is selected from ISIS NO:395177,395178,395179,395180,399807,399808,399809,399810,399811,399812,399813,399899,399900,399901,399902,399963,399964,399965,399966,399967,399968,399969,405557,405885,405886,405887,405888,405889,405890,405891,405892,405949,405950,405951,405952,405953,405954,405955,405956,405957,405958,405959,405960,405961,405962,405963,405964,405965,405966,405967,405968,405969,405970,405971,405972,405973,405974,408653,410540,410596,410597,410598,410599,410600,410601,410602,410603,410604,410672,410673,410674,410675,410676,410677,410678,410679,410680,410681,410682,410738,410739,410740,410770 or 410771.

In certain embodiments, target region is the Nucleotide 20633-20660 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20633-20660 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,322,323,324 or 325 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20633-20660 of target SEQ ID NO:2 is selected from ISIS NO:399807,399963,405951,405952,405953 or 410738.

In certain embodiments, target region is the Nucleotide 20635-20781 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20635-20781 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,44,45,46,47,48,49,50,51,87,119,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20635-20781 of target SEQ IDNO:2 is selected from ISIS NO:395177,395178,395179,395180,399807,399808,399809,399810,399811,399812,399813,399899,399900,399901,399902,399963,399964,399965,399966,399967,399968,399969,405557,405885,405886,405887,405888,405889,405890,405891,405892,405952,405953,405954,405955,405956,405957,405958,405959,405960,405961,405962,405963,405964,405965,405966,405967,405968,405969,405970,405971,405972,405973,405974,408653,410540,410596,410597,410598,410599,410600,410601,410602,410603,410604,410672,410673,410674,410675,410676,410677,410678,410679,410680,410681,410682,410738,410739,410740 or 410770.

In certain embodiments, target region is the Nucleotide 20643-20662 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20643-20662 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:326.In some such embodiment, the antisense compounds of the Nucleotide 20643-20662 of target SEQ ID NO:2 is selected from ISIS NO:405954.

In certain embodiments, target region is the Nucleotide 20657-20676 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20657-20676 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:327.In some such embodiment, the antisense compounds of the Nucleotide 20657-20676 of target SEQ ID NO:2 is selected from ISIS NO:410770.

In certain embodiments, target region is the Nucleotide 20670-20697 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20670-20697 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:328,329,330,331 or 332 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20670-20697 of target SEQ ID NO:2 is selected from ISIS NO:405955,405956,405957,405958 or 405959.

In certain embodiments, target region is the Nucleotide 20680-20706 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20680-20706 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,333,334,335 or 336 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20680-20706 of target SEQ ID NO:2 is selected from ISIS NO:399808,399964,405960,405961,405962 or 410739.

In certain embodiments, target region is the Nucleotide 20683-20781 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20683-20781 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,45,46,47,48,49,50,51,87,119,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20683-20781 of target SEQ IDNO:2 is selected from ISIS NO:395177,395178,395179,395180,399808,399809,399810,399811,399812,399813,399899,399900,399901,399902,399964,399965,399966,399967,399968,399969,405557,405885,405886,405887,405888,405889,405890,405891,405892,405962,405963,405964,405965,405966,405967,405968,405969,405970,405971,405972,405973,405974,408653,410540,410596,410597,410598,410599,410600,410601,410602,410603,410604,410672,410673,410674,410675,410676,410677,410678,410679,410680,410681,410682,410739 or 410740.

In certain embodiments, target region is the Nucleotide 20689-20715 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20689-20715 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:45,46,337 or 338 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20689-20715 of target SEQ ID NO:2 is selected from ISIS NO:395177,399809,399899,399965,405963 or 405964.

In certain embodiments, target region is the Nucleotide 20698-20725 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20698-20725 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:47,47,339,340,341 or 342 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20698-20725 of target SEQ ID NO:2 is selected from ISIS NO:399810,399966,405965,405966,405967 or 405968.

In certain embodiments, target region is the Nucleotide 20709-20736 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20709-20736 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:48,48,343,344,345 or 346 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20709-20736 of target SEQ ID NO:2 is selected from ISIS NO:399811,399967,405885,405969,405970 or 410740.

In certain embodiments, target region is the Nucleotide 20717-20744 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20717-20744 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,346,347,348,349,350,351,352 or 353 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20717-20744 of target SEQ ID NO:2 is selected from ISISNO:399812,399968,405885,405886,405887,405888,405889,405890,405891,405892,410596,410597,410598,410599,410600,410601,410672,410673,410674,410675,410676,410677 or 410678.

In certain embodiments, target region is the Nucleotide 20718-20745 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20718-20745 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,347,348,349,350,351,352 or 353 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20718-20745 of target SEQ ID NO:2 is selected from ISIS NO:395178,399812,399900,399968,405557,405886,405887,405888,405889,405890,405891,405892,410596,410597,410598,410599,410600,410601,410672,410673,410674,410675,410676,410677,410678 or 410679.

In certain embodiments, target region is the Nucleotide 20719-20746 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20719-20746 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,348,349,350,351,352,353 or 354 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20719-20746 of target SEQ ID NO:2 is selected from ISIS NO:395178,399812,399900,399968,405557,405887,405888,405889,405890,405891,405892,408653,410596,410597,410598,410599,410600,410601,410602,410672,410673,410674,410675,410676,410677,410678,410679 or 410680.

In certain embodiments, target region is the Nucleotide 20720-20747 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20720-20747 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,349,350,351,352,353,354 or 355 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20720-20747 of target SEQ ID NO:2 is selected from ISIS NO:395178,399812,399900,399968,405557,405888,405889,405890,405891,405892,405971,408653,410597,410598,410599,410600,410601,410602,410603,410673,410674,410675,410676,410677,410678,410679,410680 or 410681.

In certain embodiments, target region is the Nucleotide 20721-20748 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20721-20748 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,350,351,352,353,354,355 or 356 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20721-20748 of target SEQ ID NO:2 is selected from ISIS NO:395178,399812,399900,399968,405557,405889,405890,405891,405892,405971,408653,410540,410598,410599,410600,410601,410602,410603,410604,410674,410675,410676,410677,410678,410679,410680,410681 or 410682.

In certain embodiments, target region is the Nucleotide 20722-20749 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20722-20749 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,350,351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20722-20749 of target SEQ ID NO:2 is selected from ISISNO:395178,399900,405557,405889,405890,405891,405892,405971,405972,408653,410540,410598,410599,410600,410601,410602,410603,410604,410675,410676,410677,410678,410679,410680,410681 or 410682.

In certain embodiments, target region is the Nucleotide 20727-20752 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20727-20752 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:87,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20727-20752 of target SEQ ID NO:2 is selected from ISIS NO:395179,399901,405971,405972,408653,410540,410602,410603,410604,410680,410681 or 410682.

In certain embodiments, target region is the Nucleotide 20735-20759 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20735-20759 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:51,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20735-20759 of target SEQ ID NO:2 is selected from ISIS NO:399813,399969,405973 or 405974.

In certain embodiments, target region is the Nucleotide 20762-21014 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20762-21014 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:93,119 or 360 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 20762-21014 of target SEQ ID NO:2 is selected from ISIS NO:395180,399864,399902,400020 or 410771.

In certain embodiments, target region is the Nucleotide 20785-21014 of SEQ ID NO:2.In certain embodiments, the Nucleotide 20785-21014 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:93 or 360.In some such embodiment, the antisense compounds of the Nucleotide 20785-21014 of target SEQ ID NO:2 is selected from ISIS NO:399864,400020 or 410771.

In certain embodiments, target region is the Nucleotide 21082-21107 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21082-21107 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:95 or 361.In some such embodiment, the antisense compounds of the Nucleotide 21082-21107 of target SEQ ID NO:2 is selected from ISIS NO:399865,400021 or 405975.

In certain embodiments, target region is the Nucleotide 21082-21152 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21082-21152 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:53,54,95,361,362,363,364,365,366,367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21082-21152 of target SEQ ID NO:2 is selected from ISIS NO:395182,399814,399865,399904,399970,400021,405975,405976,405977,405978,405979,405980,405981,405982,405983,410741 or 410772.

In certain embodiments, target region is the Nucleotide 21091-21114 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21091-21114 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:53,362 or 363 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21091-21114 of target SEQ ID NO:2 is selected from ISIS NO:399814,399970,405976 or 405977.

In certain embodiments, target region is the Nucleotide 21118-21144 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21118-21144 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:54,365,366 or 367 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21118-21144 of target SEQ ID NO:2 is selected from ISIS NO:395182,399904,405978,405979 or 405980.

In certain embodiments, target region is the Nucleotide 21127-21152 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21127-21152 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21127-21152 of target SEQ ID NO:2 is selected from ISIS NO:405981,405982,405983 or 410741.

In certain embodiments, target region is the Nucleotide 21181-21209 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21181-21209 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,372,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21181-21209 of target SEQ ID NO:2 is selected from ISIS NO:399815,399971,405564,405641,405984,405985,405986 or 405987.

In certain embodiments, target region is the Nucleotide 21181-21211 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21181-21211 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,56,372,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21181-21211 of target SEQ ID NO:2 is selected from ISIS NO:399815,399816,399971,399972,405564,405641,405984,405985,405986 or 405987.

In certain embodiments, target region is the Nucleotide 21183-21211 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21183-21211 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,56,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21183-21211 of target SEQ ID NO:2 is selected from ISIS NO:399815,399816,399971,399972,405564,405641,405985,405986 or 405987.

In certain embodiments, target region is the Nucleotide 21481-21500 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21481-21500 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:143.In some such embodiment, the antisense compounds of the Nucleotide 21481-21500 of target SEQ ID NO:2 is selected from ISIS NO:399866 or 400022.

In certain embodiments, target region is the Nucleotide 21589-21608 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21589-21608 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:89.In some such embodiment, the antisense compounds of the Nucleotide 21589-21608 of target SEQ ID NO:2 is selected from ISIS NO:399867 or 400023.

In certain embodiments, target region is the Nucleotide 21692-21719 of SEQ ID NO:2.In certain embodiments, the Nucleotide 21692-21719 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:123,448,449,450,451,452,453,454 or 455 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 21692-21719 of target SEQ ID NO:2 is selected from ISISNO:399868,400024,406478,406479,406480,406481,406482,406483,406484 or 406485.

In certain embodiments, target region is the Nucleotide 22000-22227 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22000-22227 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,389,390,391,392,393,394,395 or 396 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22000-22227 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,410550,410551,410552,410553,410554,410555,410616,410617,410618,410619,410620,410621,410622,410623,410695,410696,410697,410698,410699,410700,410701,410702 or 410703.

In certain embodiments, target region is the Nucleotide 22096-22115 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22096-22115 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:57.In some such embodiment, the antisense compounds of the Nucleotide 22096-22115 of target SEQ ID NO:2 is selected from ISIS NO:395183 or 399905.

In certain embodiments, target region is the Nucleotide 22096-22223 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22096-22223 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:57,58,59,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391 or 392 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22096-22223 of target SEQ IDNO:2 is selected from ISIS NO:395183,395184,395185,399905,399906,399907,405988,405989,405990,410541,410542,410543,410544,410545,410546,410547,410548,410549,410550,410551,410552,410553,410605,410606,410607,410608,410609,410610,410611,410612,410613,410614,410615,410616,410617,410618,410619,410683,410684,410685,410686,410687,410688,410689,410690,410691,410692,410693,410694,410695,410696,410697,410698,410699 or 410773.

In certain embodiments, target region is the Nucleotide 22096-22311 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22096-22311 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:57,58,59,126,126,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,401,401,402,402,402,403,403,403,404,404,404,405,405,405 or 406 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22096-22311 of target SEQ IDNO:2 is selected from ISIS NO:395183,395184,395185,395225,399905,399906,399907,399947,405988,405989,405990,405991,405992,405993,405994,405995,410541,410542,410543,410544,410545,410546,410547,410548,410549,410550,410551,410552,410553,410554,410555,410556,410557,410558,410559,410560,410561,410605,410606,410607,410608,410609,410610,410611,410612,410613,410614,410615,410616,410617,410618,410619,410620,410621,410622,410623,410624,410625,410626,410627,410628,410629,410630,410631,410632,410683,410684,410685,410686,410687,410688,410689,410690,410691,410692,410693,410694,410695,410696,410697,410698,410699,410700,410701,410702,410703,410704,410705,410706,410707,410708,410709,410710,410711,410712,410773 or 410774.

In certain embodiments, target region is the Nucleotide 22133-22160 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22133-22160 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:376,377,378,379,380,381,382,383 or 384 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22133-22160 of target SEQ ID NO:2 is selected from ISISNO:405988,405989,410541,410542,410543,410544,410545,410546,410547,410605,410606,410607,410608,410609,410610,410611,410612,410613,410683,410684,410685,410686,410687,410688,410689,410690 or 410691.

In certain embodiments, target region is the Nucleotide 22133-22163 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22133-22163 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,376,377,378,379,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22133-22163 of target SEQ ID NO:2 is selected from ISIS NO:395184,399906,405988,405989,405990,410541,410542,410543,410544,410545,410546,410547,410548,410605,410606,410607,410608,410609,410610,410611,410612,410613,410614,410683,410684,410685,410686,410687,410688,410689,410690,410691,410692 or 410693.

In certain embodiments, target region is the Nucleotide 22134-22161 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22134-22161 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,377,378,379,380,381,382,383 or 384 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22134-22161 of target SEQ ID NO:2 is selected from ISISNO:395184,399906,405988,405989,410542,410543,410544,410545,410546,410547,410606,410607,410608,410609,410610,410611,410612,410613,410684,410685,410686,410687,410688,410689,410690,410691 or 410692.

In certain embodiments, target region is the Nucleotide 22135-22162 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22135-22162 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,378,379,380,381,382,383,384 or 385 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22135-22162 of target SEQ ID NO:2 is selected from ISISNO:395184,399906,405988,405989,410543,410544,410545,410546,410547,410548,410607,410608,410609,410610,410611,410612,410613,410614,410685,410686,410687,410688,410689,410690,410691,410692 or 410693.

In certain embodiments, target region is the Nucleotide 22136-22163 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22136-22163 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,379,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22136-22163 of target SEQ ID NO:2 is selected from ISISNO:395184,399906,405988,405989,405990,410544,410545,410546,410547,410548,410608,410609,410610,410611,410612,410613,410614,410686,410687,410688,410689,410690,410691,410692 or 410693.

In certain embodiments, target region is the Nucleotide 22137-22163 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22137-22163 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,380,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22137-22163 of target SEQ ID NO:2 is selected from ISIS NO:395184,399906,405988,405989,405990,410545,410546,410547,410548,410609,410610,410611,410612,410613,410614,410687,410688,410689,410690,410691,410692 or 410693.

In certain embodiments, target region is the Nucleotide 22138-22163 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22138-22163 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:58,381,382,383,384,385 or 386 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22138-22163 of target SEQ ID NO:2 is selected from ISIS NO:395184,399906,405988,405989,405990,410546,410547,410548,410610,410611,410612,410613,410614,410688,410689,410690,410691,410692 or 410693.

In certain embodiments, target region is the Nucleotide 22189-22239 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22189-22239 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405 or 406 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22189-22239 of target SEQ ID NO:2 is selected from ISIS NO:395185,399907,405991,405992,405993,405994,405995,410549,410550,410551,410552,410553,410554,410555,410556,410557,410558,410559,410560,410561,410615,410616,410617,410618,410619,410620,410621,410622,410623,410624,410625,410626,410627,410628,410629,410630,410631,410632,410694,410695,410696,410697,410698,410699,410700,410701,410702,410703,410704,410705,410706,410707,410708,410709,410710,410711,410712,410773 or 410774.

In certain embodiments, target region is the Nucleotide 22199-22226 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22199-22226 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,388,389,390,391,392,393,394 or 395 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22199-22226 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,410549,410550,410551,410552,410553,410554,410555,410615,410616,410617,410618,410619,410620,410621,410622,410694,410695,410696,410697,410698,410699,410700,410701 or 410702.

In certain embodiments, target region is the Nucleotide 22199-22227 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22199-22227 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,388,389,390,391,392,393,394,395 or 396 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22199-22227 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,410549,410550,410551,410552,410553,410554,410555,410615,410616,410617,410618,410619,410620,410621,410622,410623,410694,410695,410696,410697,410698,410699,410700,410701,410702 or 410703.

In certain embodiments, target region is the Nucleotide 22200-22227 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22200-22227 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,389,390,391,392,393,394,395 or 396 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22200-22227 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,410550,410551,410552,410553,410554,410555,410616,410617,410618,410619,410620,410621,410622,410623,410695,410696,410697,410698,410699,410700,410701,410702 or 410703.

In certain embodiments, target region is the Nucleotide 22201-22228 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22201-22228 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,390,391,392,393,394,395,396 or 397 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22201-22228 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,410551,410552,410553,410554,410555,410556,410617,410618,410619,410620,410621,410622,410623,410624,410696,410697,410698,410699,410700,410701,410702,410703 or 410704.

In certain embodiments, target region is the Nucleotide 22202-22229 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22202-22229 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,391,392,393,394,395,396,397 or 398 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22202-22229 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,405993,410552,410553,410554,410555,410556,410618,410619,410620,410621,410622,410623,410624,410625,410697,410698,410699,410700,410701,410702,410703,410704 or 410705.

In certain embodiments, target region is the Nucleotide 22203-22230 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22203-22230 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,392,393,394,395,396,397,398 or 399 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22203-22230 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,405993,410553,410554,410555,410556,410557,410619,410620,410621,410622,410623,410624,410625,410626,410698,410699,410700,410701,410702,410703,410704,410705 or 410706.

In certain embodiments, target region is the Nucleotide 22204-22231 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22204-22231 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:59,393,394,395,396,397,398,399 or 400 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22204-22231 of target SEQ ID NO:2 is selected from ISISNO:395185,399907,405991,405992,405993,405994,410554,410555,410556,410557,410620,410621,410622,410623,410624,410625,410626,410627,410699,410700,410701,410702,410703,410704,410705,410706 or 410707.

In certain embodiments, target region is the Nucleotide 22205-22232 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22205-22232 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:393,394,395,396,397,398,399,400 or 401 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22205-22232 of target SEQ ID NO:2 is selected from ISISNO:405991,405992,405993,405994,410554,410555,410556,410557,410558,410620,410621,410622,410623,410624,410625,410626,410627,410628,410700,410701,410702,410703,410704,410705,410706,410707 or 410708.

In certain embodiments, target region is the Nucleotide 22206-22233 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22206-22233 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:394,395,396,397,398,399,400,401 or 402 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22206-22233 of target SEQ ID NO:2 is selected from ISISNO:405991,405992,405993,405994,405995,410555,410556,410557,410558,410621,410622,410623,410624,410625,410626,410627,410628,410629,410701,410702,410703,410704,410705,410706,410707,410708 or 410709.

In certain embodiments, target region is the Nucleotide 22207-22234 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22207-22234 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:395,396,397,398,399,400,401,402 or 403 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22207-22234 of target SEQ ID NO:2 is selected from ISISNO:405992,405993,405994,405995,410555,410556,410557,410558,410559,410622,410623,410624,410625,410626,410627,410628,410629,410630,410702,410703,410704,410705,410706,410707,410708,410709 or 410710.

In certain embodiments, target region is the Nucleotide 22208-22235 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22208-22235 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:396,397,398,399,400,401,402,403 or 404 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22208-22235 of target SEQ ID NO:2 is selected from ISISNO:405992,405993,405994,405995,410556,410557,410558,410559,410560,410623,410624,410625,410626,410627,410628,410629,410630,410631,410703,410704,410705,410706,410707,410708,410709,410710 or 410711.

In certain embodiments, target region is the Nucleotide 22209-22236 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22209-22236 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:397,398,399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22209-22236 of target SEQ ID NO:2 is selected from ISISNO:405993,405994,405995,410556,410557,410558,410559,410560,410561,410624,410625,410626,410627,410628,410629,410630,410631,410632,410704,410705,410706,410707,410708,410709,410710,410711 or 410712.

In certain embodiments, target region is the Nucleotide 22210-22236 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22210-22236 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:398,399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22210-22236 of target SEQ ID NO:2 is selected from ISIS NO:405993,405994,405995,410557,410558,410559,410560,410561,410625,410626,410627,410628,410629,410630,410631,410632,410705,410706,410707,410708,410709,410710,410711 or 410712.

In certain embodiments, target region is the Nucleotide 22210-22239 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22210-22239 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:398,399,400,401,402,403,404,405 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22210-22239 of target SEQ ID NO:2 is selected from ISISNO:405993,405994,405995,410557,410558,410559,410560,410561,410625,410626,410627,410628,410629,410630,410631,410632,410705,410706,410707,410708,410709,410710,410711,410712 or 410774.

In certain embodiments, target region is the Nucleotide 22211-22236 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22211-22236 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:399,400,401,402,403,404 or 405 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22211-22236 of target SEQ ID NO:2 is selected from ISIS NO:405994,405995,410557,410558,410559,410560,410561,410626,410627,410628,410629,410630,410631,410632,410706,410707,410708,410709,410710,410711 or 410712.

In certain embodiments, target region is the Nucleotide 22212-22239 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22212-22239 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:400,401,402,403,404,405 or 406 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 22212-22239 of target SEQ ID NO:2 is selected from ISIS NO:405994,405995,410558,410559,410560,410561,410627,410628,410629,410630,410631,410632,410707,410708,410709,410710,410711,410712 or 410774.

In certain embodiments, target region is the Nucleotide 22292-22311 of SEQ ID NO:2.In certain embodiments, the Nucleotide 22292-22311 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:126.In some such embodiment, the antisense compounds of the Nucleotide 22292-22311 of target SEQ ID NO:2 is selected from ISIS NO:395225 or 399947.

In certain embodiments, target region is the Nucleotide 23985-24054 of SEQ ID NO:2.In certain embodiments, the Nucleotide 23985-24054 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:408,409 or 410 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 23985-24054 of target SEQ ID NO:2 is selected from ISIS NO:410776,410777 or 410778.

In certain embodiments, target region is the Nucleotide 24035-24134 of SEQ ID NO:2.In certain embodiments, the Nucleotide 24035-24134 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,410,411,412,413,414,415 or 416 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 24035-24134 of target SEQ ID NO:2 is selected from ISIS NO:395186,399817,399908,399973,405996,405997,410562,410563,410564,410633,410634,410635,410636,410713,410714,410715,410716,410717,410718,410778 or 410779.

In certain embodiments, target region is the Nucleotide 24095-24121 of SEQ ID NO:2.In certain embodiments, the Nucleotide 24095-24121 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414 or 415 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 24095-24121 of target SEQ IDNO:2 is selected from ISIS NO:395186,399817,399908,399973,405996,405997,410562,410563,410564,410633,410634,410635,410636,410713,410714,410715,410716,410717 or 410718.

In certain embodiments, target region is the Nucleotide 24858-24877 of SEQ ID NO:2.In certain embodiments, the Nucleotide 24858-24877 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:147.In some such embodiment, the antisense compounds of the Nucleotide 24858-24877 of target SEQ ID NO:2 is selected from ISIS NO:395226 or 399948.

In certain embodiments, target region is the Nucleotide 24907-24926 of SEQ ID NO:2.In certain embodiments, the Nucleotide 24907-24926 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:118.In some such embodiment, the antisense compounds of the Nucleotide 24907-24926 of target SEQ ID NO:2 is selected from ISIS NO:399869 or 400025.

In certain embodiments, target region is the Nucleotide 25413-25432 of SEQ ID NO:2.In certain embodiments, the Nucleotide 25413-25432 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:114.In some such embodiment, the antisense compounds of the Nucleotide 25413-25432 of target SEQ ID NO:2 is selected from ISIS NO:399870 or 400026.

In certain embodiments, target region is the Nucleotide 25994-26013 of SEQ ID NO:2.In certain embodiments, the Nucleotide 25994-26013 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:418.In some such embodiment, the antisense compounds of the Nucleotide 25994-26013 of target SEQ ID NO:2 is selected from ISIS NO:410781.

In certain embodiments, target region is the Nucleotide 26112-26139 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26112-26139 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425 or 426 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26112-26139 of target SEQ ID NO:2 is selected from ISISNO:395187,399909,405998,410565,410566,410567,410568,410569,410570,410571,410637,410638,410639,410640,410641,410642,410643,410644,410719,410720,410721,410722,410723,410724,410725,410726 or 410727.

In certain embodiments, target region is the Nucleotide 26112-26161 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26112-26161 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425,426,427,428,429 or 430 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26112-26161 of target SEQ ID NO:2 is selected from ISIS NO:395187,399909,405998,410565,410566,410567,410568,410569,410570,410571,410572,410573,410637,410638,410639,410640,410641,410642,410643,410644,410645,410646,410719,410720,410721,410722,410723,410724,410725,410726,410727,410728,410729,410782 or 410783.

In certain embodiments, target region is the Nucleotide 26112-27303 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26112-27303 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,112,122,135,153,154,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445 or 446 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26112-27303 of target SEQ IDNO:2 is selected from ISIS NO:395187,395188,395189,395190,395191,395192,395193,395194,395195,395196,395197,395198,395199,399818,399819,399820,399821,399822,399823,399824,399825,399909,399910,399911,399912,399913,399914,399915,399916,399917,399918,399919,399920,399921,399974,399975,399976,399977,399978,399979,399980,399981,405893,405894,405895,405896,405897,405898,405899,405900,405901,405902,405903,405904,405905,405906,405907,405908,405998,410565,410566,410567,410568,410569,410570,410571,410572,410573,410637,410638,410639,410640,410641,410642,410643,410644,410645,410646,410719,410720,410721,410722,410723,410724,410725,410726,410727,410728,410729,410782 or 410783.

In certain embodiments, target region is the Nucleotide 26113-26140 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26113-26140 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,420,421,422,423,424,425,426 or 427 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26113-26140 of target SEQ ID NO:2 is selected from ISISNO:395187,399909,405998,410566,410567,410568,410569,410570,410571,410572,410638,410639,410640,410641,410642,410643,410644,410645,410720,410721,410722,410723,410724,410725,410726,410727 or 410728.

In certain embodiments, target region is the Nucleotide 26114-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26114-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,421,422,423,424,425,426,427 or 248 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26114-26141 of target SEQ ID NO:2 is selected from ISISNO:395187,399909,405998,410567,410568,410569,410570,410571,410572,410573,410639,410640,410641,410642,410643,410644,410645,410646,410721,410722,410723,410724,410725,410726,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 26115-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26115-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,422,423,424,425,426,427 or 248 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26115-26141 of target SEQ ID NO:2 is selected from ISIS NO:395187,399909,405998,410568,410569,410570,410571,410572,410573,410640,410641,410642,410643,410644,410645,410646,410722,410723,410724,410725,410726,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 26116-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26116-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,423,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26116-26141 of target SEQ ID NO:2 is selected from ISIS NO:395187,399909,405998,410569,410570,410571,410572,410573,410641,410642,410643,410644,410645,410646,410723,410724,410725,410726,410727 or 410728.

In certain embodiments, target region is the Nucleotide 26117-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26117-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26117-26141 of target SEQ IDNO:2 is selected from ISIS NO:395187,399909,405998,410570,410571,410572,410573,410642,410643,410644,410645,410646,410724,410725,410726,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 26117-26475 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26117-26475 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,63,64,65,66,67,122,153,154,424,425,426,427,428,429 or 430 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26117-26475 of target SEQ ID NO:2 is selected from ISIS NO:395187,395188,395189,395190,395191,395192,399818,399819,399820,399909,399910,399911,399912,399913,399914,399974,399975,399976,405998,410570,410571,410572,410573,410642,410643,410644,410645,410646,410724,410725,410726,410727,410728,410729,410782 or 410783.

In certain embodiments, target region is the Nucleotide 26118-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26118-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26118-26141 of target SEQ ID NO:2 is selected from ISIS NO:405998,410570,410571,410572,410573,410642,410643,410644,410645,410646,410725,410726,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 26120-26141 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26120-26141 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26120-26141 of target SEQ ID NO:2 is selected from ISIS NO:405998,410572,410573,410644,410645,410646,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 26132-26151 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26132-26151 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:429.In some such embodiment, the antisense compounds of the Nucleotide 26132-26151 of target SEQ ID NO:2 is selected from ISIS NO:410782.

In certain embodiments, target region is the Nucleotide 26142-26161 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26142-26161 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:430.In some such embodiment, the antisense compounds of the Nucleotide 26142-26161 of target SEQ ID NO:2 is selected from ISIS NO:410783.

In certain embodiments, target region is the Nucleotide 26217-26241 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26217-26241 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:63 or 154.In some such embodiment, the antisense compounds of the Nucleotide 26217-26241 of target SEQ ID NO:2 is selected from ISIS NO:395188,399818 or 399910.

In certain embodiments, target region is the Nucleotide 26311-26335 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26311-26335 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:64 or 65.In some such embodiment, the antisense compounds of the Nucleotide 26311-26335 of target SEQ ID NO:2 is selected from ISIS NO:395189,399819,399911 or 399975.

In certain embodiments, target region is the Nucleotide 26389-26432 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26389-26432 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:66,67 or 122 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26389-26432 of target SEQ ID NO:2 is selected from ISIS NO:395190,395191,399820,399912,399913 or 399976.

In certain embodiments, target region is the Nucleotide 26456-26576 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26456-26576 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:68 or 153.In some such embodiment, the antisense compounds of the Nucleotide 26456-26576 of target SEQ ID NO:2 is selected from ISIS NO:395192,395193,399914 or 399915.

In certain embodiments, target region is the Nucleotide 26635-26662 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26635-26662 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:69,431,432,433,434,435,436,437 or 438 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26635-26662 of target SEQ ID NO:2 is selected from ISISNO:395194,399916,405893,405894,405895,405896,405897,405898,405899 or 405900.

In certain embodiments, target region is the Nucleotide 26707-26734 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26707-26734 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:70,71,439,440,441,442,443 or 444 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26707-26734 of target SEQ ID NO:2 is selected from ISIS NO:395195,399821,399917,399977,405901,405902,405903,405904,405905 or 405906.

In certain embodiments, target region is the Nucleotide 26707-26736 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26707-26736 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:70,71,439,440,441,442,443,444,445 or 446 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26707-26736 of target SEQ ID NO:2 is selected from ISISNO:395195,399821,399917,399977,405901,405902,405903,405904,405905,405906,405907 or 405908.

In certain embodiments, target region is the Nucleotide 26790-26820 of SEQ ID NO:2.In certain embodiments, the Nucleotide 26790-26820 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:72,73 or 135 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 26790-26820 of target SEQ ID NO:2 is selected from ISIS NO:395196,399822,399823,399918,399978 or 399979.

In certain embodiments, target region is the Nucleotide 27034-27263 of SEQ ID NO:2.In certain embodiments, the Nucleotide 27034-27263 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:74,75 or 112 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 27034-27263 of target SEQ ID NO:2 is selected from ISIS NO:395197,395198,399824,399919,399920 or 399980.

In certain embodiments, target region is the Nucleotide 27279-27303 of SEQ ID NO:2.In certain embodiments, the Nucleotide 27279-27303 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:76 or 77.In some such embodiment, the antisense compounds of the Nucleotide 27279-27303 of target SEQ ID NO:2 is selected from ISIS NO:395199,399825,399921 or 399981.

In certain embodiments, target region is the Nucleotide 27350-27376 of SEQ ID NO:2.In certain embodiments, the Nucleotide 27350-27376 of antisense compounds target SEQ ID NO:2.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:78 or 99.In some such embodiment, the antisense compounds of the Nucleotide 27350-27376 of target SEQ ID NO:2 is selected from ISIS NO:395200,399826,399922 or 399982.

In certain embodiments, the antisense compounds target has

Accession number AK124635.1 is (early than being stored on September 8th, 2003

And as SEQ ID NO:3 income this paper) the PCSK9 nucleic acid of sequence.In some such embodiment, antisense oligonucleotide target SEQ ID NO:3.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:3 and SEQ ID NO:3 at least 90% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ IDNO:3 and SEQ ID NO:3 at least 95% complementation.In some such embodiment, the antisense oligonucleotide of target SEQ ID NO:3 and SEQ ID NO:3100% complementation.In some such embodiment, antisense oligonucleotide comprises the nucleotide sequence that is selected from the listed nucleotide sequence of table 11.

Table 11: the nucleotide sequence of target AK124635.1 (SEQ ID NO:3)

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				85	155	174	ACAAATTCCCAGACTCAGCA
100	220	239	ATCTCAGGACAGGTGAGCAA
				116	234	253	GAGTAGAGATTCTCATCTCA
129	290	309	GTGCCATCTGAACAGCACCT
				117	302	321	GAGTCTTCTGAAGTGCCATC
81	377	396	AAGCAGGGCCTCAGGTGGAA
				110	400	419	CCTGGAACCCCTGCAGCCAG
152	451	470	TTCAGGCAGGTTGCTGCTAG
				83	460	479	AAGGAAGACTTCAGGCAGGT
140	472	491	TCAGCCAGGCCAAAGGAAGA
				137	586	605	TAGGGAGAGCTCACAGATGC
136	596	615	TAGGAGAAAGTAGGGAGAGC
				132	653	672	TAAAAGCTGCAAGAGACTCA
139	741	760	TCAGAGAAAACAGTCACCGA
				92	871	890	AGAGACAGGAAGCTGCAGCT
142	878	897	TCATTTTAGAGACAGGAAGC
				113	915	934	GAATAACAGTGATGTCTGGC
138	968	987	TCACAGCTCACCGAGTCTGC
				98	998	1017	AGTGTAAAATAAAGCCCCTA
96	1075	1094	AGGACCCAAGTCATCCTGCT
				124	1105	1124	GGCCATCAGCTGGCAATGCT
82	1144	1163	AAGGAAAGGGAGGCCTAGAG
				133	1149	1168	TAGACAAGGAAAGGGAGGCC
103	1155	1174	ATTTCATAGACAAGGAAAGG
				155	1275	1294	CTTATAGTTAACACACAGAA
156	1283	1302	AAGTCAACCTTATAGTTAAC
				146	1315	1334	TGACATTTGTGGGAGAGGAG
161	1322	1341	TCCAAGGTGACATTTGTGGG
				215	1351	1370	ATACACCTCCACCAGGCTGC
216	1362	1381	GTGTCTAGGAGATACACCTC
				19	1365	1384	CTGGTGTCTAGGAGATACAC
217	1367	1386	TGCTGGTGTCTAGGAGATAC
				20	1370	1389	GTATGCTGGTGTCTAGGAGA
21	1390	1409	GATTTCCCGGTGGTCACTCT
				218	1392	1411	TCGATTTCCCGGTGGTCACT
219	1393	1412	CTCGATTTCCCGGTGGTCAC
				220	1394	1413	CCTCGATTTCCCGGTGGTCA
221	1395	1414	CCCTCGATTTCCCGGTGGTC
				22	1396	1415	GCCCTCGATTTCCCGGTGGT
222	1397	1416	TGCCCTCGATTTCCCGGTGG
				223	1398	1417	CTGCCCTCGATTTCCCGGTG
224	1399	1418	CCTGCCCTCGATTTCCCGGT
				225	1400	1419	CCCTGCCCTCGATTTCCCGG
226	1404	1423	ATGACCCTGCCCTCGATTTC
				227	1406	1425	CCATGACCCTGCCCTCGATT

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				228	1408	1427	GACCATGACCCTGCCCTCGA
23	1410	1429	GTGACCATGACCCTGCCCTC
				229	1412	1431	CGGTGACCATGACCCTGCCC
230	1414	1433	GTCGGTGACCATGACCCTGC
				231	1416	1435	AAGTCGGTGACCATGACCCT
232	1418	1437	CGAAGTCGGTGACCATGACC
				24	1420	1439	CTCGAAGTCGGTGACCATGA
233	1428	1447	GGCACATTCTCGAAGTCGGT
				25	1453	1472	GTGGAAGCGGGTCCCGTCCT
234	1463	1482	TGGCCTGTCTGTGGAAGCGG
				235	1490	1509	GGTGGGTGCCATGACTGTCA
236	1493	1512	CCAGGTGGGTGCCATGACTG
				237	1497	1516	CCTGCCAGGTGGGTGCCATG
26	1500	1519	ACCCCTGCCAGGTGGGTGCC
				238	1502	1521	CCACCCCTGCCAGGTGGGTG
27	1505	1524	TGACCACCCCTGCCAGGTGG
				239	1507	1526	GCTGACCACCCCTGCCAGGT
240	1515	1534	TCCCGGCCGCTGACCACCCC
				241	1519	1538	GGCATCCCGGCCGCTGACCA
242	1522	1541	GCCGGCATCCCGGCCGCTGA
				243	1527	1546	GCCACGCCGGCATCCCGGCC
244	1528	1547	GGCCACGCCGGCATCCCGGC
				245	1529	1548	TGGCCACGCCGGCATCCCGG
246	1530	1549	TTGGCCACGCCGGCATCCCG
				247	1531	1550	CTTGGCCACGCCGGCATCCC
248	1532	1551	CCTTGGCCACGCCGGCATCC
				249	1533	1552	CCCTTGGCCACGCCGGCATC
28	1534	1553	ACCCTTGGCCACGCCGGCAT
				447	1534	1553	ACCCTTGGTCACGCCGGCAT
250	1535	1554	CACCCTTGGCCACGCCGGCA
				251	1536	1555	GCACCCTTGGCCACGCCGGC
252	1537	1556	GGCACCCTTGGCCACGCCGG
				253	1538	1557	TGGCACCCTTGGCCACGCCG
254	1539	1558	CTGGCACCCTTGGCCACGCC
				255	1540	1559	GCTGGCACCCTTGGCCACGC
256	1545	1564	CGCATGCTGGCACCCTTGGC
				257	1566	1585	CAGTTGAGCACGCGCAGGCT
258	1568	1587	GGCAGTTGAGCACGCGCAGG
				29	1570	1589	TTGGCAGTTGAGCACGCGCA
259	1572	1591	CCTTGGCAGTTGAGCACGCG
				30	1575	1594	TTCCCTTGGCAGTTGAGCAC
260	1577	1596	CCTTCCCTTGGCAGTTGAGC
				261	1581	1600	GTGCCCTTCCCTTGGCAGTT
262	1583	1602	CCGTGCCCTTCCCTTGGCAG
				263	1594	1613	GGTGCCGCTAACCGTGCCCT
264	1606	1625	CAGGCCTATGAGGGTGCCGC
				31	1607	1626	CCAGGCCTATGAGGGTGCCG
458	1609	1622	GCCTATGAGGGTGC
				459	1614	1627	TCCAGGCCTATGAG
265	1618	1637	CCGAATAAACTCCAGGCCTA
				266	1626	1645	TGGCTTTTCCGAATAAACTC

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				32	1628	1647	GCTGGCTTTTCCGAATAAAC
267	1630	1649	CAGCTGGCTTTTCCGAATAA
				268	1632	1651	ACCAGCTGGCTTTTCCGAAT
269	1634	1653	GGACCAGCTGGCTTTTCCGA
				270	1638	1657	GGCTGGACCAGCTGGCTTTT
271	1649	1668	GTGGCCCCACAGGCTGGACC
				272	1662	1681	AGCAGCACCACCAGTGGCCC
273	1684	1703	GCTGTACCCACCCGCCAGGG
				274	1730	1749	CGACCCCAGCCCTCGCCAGG
33	1740	1759	GTGACCAGCACGACCCCAGC
				275	1742	1761	CGGTGACCAGCACGACCCCA
276	1744	1763	AGCGGTGACCAGCACGACCC
				277	1746	1765	GCAGCGGTGACCAGCACGAC
278	1748	1767	CGGCAGCGGTGACCAGCACG
				279	1749	1768	CCGGCAGCGGTGACCAGCAC
280	1752	1771	TTGCCGGCAGCGGTGACCAG
				281	1754	1773	AGTTGCCGGCAGCGGTGACC
282	1756	1775	GAAGTTGCCGGCAGCGGTGA
				283	1758	1777	CGGAAGTTGCCGGCAGCGGT
284	1760	1779	CCCGGAAGTTGCCGGCAGCG
				285	1762	1781	GTCCCGGAAGTTGCCGGCAG
306	1820	1839	GAGGCACCAATGATGTCCTC
				39	1822	1841	TGGAGGCACCAATGATGTCC
307	1824	1843	GCTGGAGGCACCAATGATGT
				308	1826	1845	TCGCTGGAGGCACCAATGAT
309	1828	1847	AGTCGCTGGAGGCACCAATG
				310	1830	1849	GCAGTCGCTGGAGGCACCAA
40	1833	1852	GCTGCAGTCGCTGGAGGCAC
				311	1835	1854	GTGCTGCAGTCGCTGGAGGC
312	1837	1856	AGGTGCTGCAGTCGCTGGAG
				313	1839	1858	GCAGGTGCTGCAGTCGCTGG
314	1840	1859	AGCAGGTGCTGCAGTCGCTG
				315	1842	1861	AAAGCAGGTGCTGCAGTCGC
41	1844	1863	ACAAAGCAGGTGCTGCAGTC
				316	1846	1865	ACACAAAGCAGGTGCTGCAG
317	1848	1867	TGACACAAAGCAGGTGCTGC
				318	1858	1877	TCCCACTCTGTGACACAAAG
101	1898	1917	ATGGCTGCAATGCCAGCCAC
				319	1900	1919	TCATGGCTGCAATGCCAGCC
42	1903	1922	GCATCATGGCTGCAATGCCA
				320	1905	1924	CAGCATCATGGCTGCAATGC
321	1907	1926	GACAGCATCATGGCTGCAAT
				322	1909	1928	CAGACAGCATCATGGCTGCA
43	1911	1930	GGCAGACAGCATCATGGCTG
				323	1913	1932	TCGGCAGACAGCATCATGGC
324	1915	1934	GCTCGGCAGACAGCATCATG
				325	1917	1936	CGGCTCGGCAGACAGCATCA
326	1919	1938	TCCGGCTCGGCAGACAGCAT
				327	1933	1952	CGGCCAGGGTGAGCTCCGGC
328	1946	1965	CTCTGCCTCAACTCGGCCAG

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				329	1948	1967	GTCTCTGCCTCAACTCGGCC
330	1950	1969	CAGTCTCTGCCTCAACTCGG
				331	1952	1971	ATCAGTCTCTGCCTCAACTC
332	1954	1973	GGATCAGTCTCTGCCTCAAC
				333	1956	1975	GTGGATCAGTCTCTGCCTCA
334	1958	1977	AAGTGGATCAGTCTCTGCCT
				44	1959	1978	GAAGTGGATCAGTCTCTGCC
335	1961	1980	GAGAAGTGGATCAGTCTCTG
				336	1963	1982	CAGAGAAGTGGATCAGTCTC
337	1965	1984	GGCAGAGAAGTGGATCAGTC
				45	1967	1986	TTGGCAGAGAAGTGGATCAG
338	1969	1988	CTTTGGCAGAGAAGTGGATC
				46	1972	1991	CATCTTTGGCAGAGAAGTGG
339	1974	1993	GACATCTTTGGCAGAGAAGT
				340	1976	1995	ATGACATCTTTGGCAGAGAA
47	1978	1997	TGATGACATCTTTGGCAGAG
				341	1980	1999	ATTGATGACATCTTTGGCAG
342	1982	2001	TCATTGATGACATCTTTGGC
				48	1985	2004	GCCTCATTGATGACATCTTT
343	1987	2006	AGGCCTCATTGATGACATCT
				344	1989	2008	CCAGGCCTCATTGATGACAT
345	1991	2010	AACCAGGCCTCATTGATGAC
				346	1993	2012	GGAACCAGGCCTCATTGATG
347	1994	2013	GGGAACCAGGCCTCATTGAT
				348	1995	2014	AGGGAACCAGGCCTCATTGA
349	1996	2015	CAGGGAACCAGGCCTCATTG
				49	1997	2016	TCAGGGAACCAGGCCTCATT
350	1998	2017	CTCAGGGAACCAGGCCTCAT
				351	1999	2018	CCTCAGGGAACCAGGCCTCA
352	2000	2019	TCCTCAGGGAACCAGGCCTC
				353	2001	2020	GTCCTCAGGGAACCAGGCCT
50	2002	2021	GGTCCTCAGGGAACCAGGCC
				354	2003	2022	TGGTCCTCAGGGAACCAGGC
355	2004	2023	CTGGTCCTCAGGGAACCAGG
				356	2005	2024	GCTGGTCCTCAGGGAACCAG
357	2006	2025	CGCTGGTCCTCAGGGAACCA
				87	2009	2028	ACCCGCTGGTCCTCAGGGAA
358	2011	2030	GTACCCGCTGGTCCTCAGGG
				359	2013	2032	CAGTACCCGCTGGTCCTCAG
51	2016	2035	GGTCAGTACCCGCTGGTCCT
				119	2038	2057	GCAGGGCGGCCACCAGGTTG
360	2061	2080	ACCTGCCCCATGGGTGCTGG
				52	2073	2092	AAACAGCTGCCAACCTGCCC
361	2075	2094	CAAAACAGCTGCCAACCTGC
				53	2078	2097	CTGCAAAACAGCTGCCAACC
362	2080	2099	TCCTGCAAAACAGCTGCCAA
				363	2082	2101	AGTCCTGCAAAACAGCTGCC
104	2085	2104	CACAGTCCTGCAAAACAGCT
				130	2095	2114	GTGCTGACCACACAGTCCTG
365	2105	2124	GGCCCCGAGTGTGCTGACCA

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				54	2108	2127	GTAGGCCCCGAGTGTGCTGA
366	2110	2129	GTGTAGGCCCCGAGTGTGCT
				367	2112	2131	CCGTGTAGGCCCCGAGTGTG
368	2114	2133	ATCCGTGTAGGCCCCGAGTG
				369	2116	2135	CCATCCGTGTAGGCCCCGAG
370	2118	2137	GGCCATCCGTGTAGGCCCCG
				371	2120	2139	GTGGCCATCCGTGTAGGCCC
372	2168	2187	CTGGAGCAGCTCAGCAGCTC
				460	2168	2181	CAGCTCAGCAGCTC
373	2170	2189	AACTGGAGCAGCTCAGCAGC
				55	2173	2192	AGAAACTGGAGCAGCTCAGC
374	2175	2194	GGAGAAACTGGAGCAGCTCA
				375	2177	2196	CTGGAGAAACTGGAGCAGCT
56	2179	2198	TCCTGGAGAAACTGGAGCAG
				408	2245	2264	GTGCCAAGGTCCTCCACCTC
409	2265	2284	TCAGCACAGGCGGCTTGTGG
				410	2295	2314	CCACGCACTGGTTGGGCTGA
60	2355	2374	CTTTGCATTCCAGACCTGGG
				411	2356	2375	ACTTTGCATTCCAGACCTGG
412	2357	2376	GACTTTGCATTCCAGACCTG
				413	2358	2377	TGACTTTGCATTCCAGACCT
414	2359	2378	TTGACTTTGCATTCCAGACC
				61	2360	2379	CTTGACTTTGCATTCCAGAC
415	2362	2381	TCCTTGACTTTGCATTCCAG
				416	2375	2394	CGGGATTCCATGCTCCTTGA
417	2405	2424	GCAGGCCACGGTCACCTGCT
				418	2442	2461	GGAGGGCACTGCAGCCAGTC
419	2560	2579	CAGATGGCAACGGCTGTCAC
				420	2561	2580	GCAGATGGCAACGGCTGTCA
421	2562	2581	AGCAGATGGCAACGGCTGTC
				422	2563	2582	CAGCAGATGGCAACGGCTGT
423	2564	2583	GCAGCAGATGGCAACGGCTG
				62	2565	2584	GGCAGCAGATGGCAACGGCT
424	2566	2585	CGGCAGCAGATGGCAACGGC
				425	2567	2586	CCGGCAGCAGATGGCAACGG
426	2568	2587	TCCGGCAGCAGATGGCAACG
				427	2569	2588	CTCCGGCAGCAGATGGCAAC
428	2570	2589	GCTCCGGCAGCAGATGGCAA
				429	2580	2599	CCAGGTGCCGGCTCCGGCAG
430	2590	2609	GAGGCCTGCGCCAGGTGCCG
				154	2665	2684	TTTTAAAGCTCAGCCCCAGC
63	2670	2689	AACCATTTTAAAGCTCAGCC
				64	2759	2778	TCAAGGGCCAGGCCAGCAGC
65	2764	2783	CCCACTCAAGGGCCAGGCCA
				122	2837	2856	GGAGGGAGCTTCCTGGCACC
66	2852	2871	ATGCCCCACAGTGAGGGAGG
				67	2861	2880	AATGGTGAAATGCCCCACAG
153	2904	2923	TTGGGAGCAGCTGGCAGCAC
				68	3005	3024	CATGGGAAGAATCCTGCCTC

SEQ ID NO	5 ' target site on the SEQ ID NO:2	3 ' target site on the SEQ ID NO:2	Sequence (5 '-3 ')
				431	3083	3102	ATGAGGGCCATCAGCACCTT
432	3084	3103	GATGAGGGCCATCAGCACCT
				433	3085	3104	AGATGAGGGCCATCAGCACC
434	3086	3105	GAGATGAGGGCCATCAGCAC
				69	3087	3106	GGAGATGAGGGCCATCAGCA
435	3088	3107	TGGAGATGAGGGCCATCAGC
				436	3089	3108	CTGGAGATGAGGGCCATCAG
437	3090	3109	GCTGGAGATGAGGGCCATCA
				438	3091	3110	AGCTGGAGATGAGGGCCATC
461	3132	3145	TTAATCAGGGAGCC
				70	3155	3174	TAGATGCCATCCAGAAAGCT
439	3157	3176	GCTAGATGCCATCCAGAAAG
				440	3158	3177	GGCTAGATGCCATCCAGAAA
441	3159	3178	TGGCTAGATGCCATCCAGAA
				442	3160	3179	CTGGCTAGATGCCATCCAGA
71	3161	3180	TCTGGCTAGATGCCATCCAG
				443	3162	3181	CTCTGGCTAGATGCCATCCA
444	3163	3182	CCTCTGGCTAGATGCCATCC
				445	3164	3183	GCCTCTGGCTAGATGCCATC
446	3165	3184	AGCCTCTGGCTAGATGCCAT
				72	3238	3257	GGCATAGAGCAGAGTAAAGG
73	3243	3262	AGCCTGGCATAGAGCAGAGT
				135	3249	3268	TAGCACAGCCTGGCATAGAG
112	3482	3501	GAAGAGGCTTGGCTTCAGAG
				74	3488	3507	AAGTAAGAAGAGGCTTGGCT
75	3692	3711	GCTCAAGGAGGGACAGTTGT
				76	3727	3746	AAAGATAAATGTCTGCTTGC
77	3732	3751	ACCCAAAAGATAAATGTCTG
				78	3798	3817	TCTTCAAGTTACAAAAGCAA
99	3805	3824	ATAAATATCTTCAAGTTACA

In certain embodiments, breach polymers antisense compounds target PCSK9 nucleic acid.In some such embodiment, breach polymers antisense compounds target SEQ ID NO:3.In some such embodiment, illustrative nucleotide sequence has 5-10-5 breach polymers motif in the table 11.Table 12 illustration the breach polymers antisense compounds of target SEQ ID NO:3, it has the 5-10-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 12: the breach polymers antisense compounds of target SEQ ID NO:3 with 5-10-5 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							395201	5-10-5	85	155	174	0	ACAAATTCCCAGACTCAGCA
399827	5-10-5	100	220	239	0	ATCTCAGGACAGGTGAGCAA
							399828	5-10-5	116	234	253	0	GAGTAGAGATTCTCATCTCA
395202	5-10-5	129	290	309	0	GTGCCATCTGAACAGCACCT
							399829	5-10-5	117	302	321	0	GAGTCTTCTGAAGTGCCATC
399830	5-10-5	81	377	396	0	AAGCAGGGCCTCAGGTGGAA

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							395203	5-10-5	110	400	419	0	CCTGGAACCCCTGCAGCCAG
395204	5-10-5	152	451	470	0	TTCAGGCAGGTTGCTGCTAG
							399831	5-10-5	83	460	479	0	AAGGAAGACTTCAGGCAGGT
395205	5-10-5	140	472	491	0	TCAGCCAGGCCAAAGGAAGA
							399832	5-10-5	137	586	605	0	TAGGGAGAGCTCACAGATGC
395206	5-10-5	136	596	615	0	TAGGAGAAAGTAGGGAGAGC
							395207	5-10-5	132	653	672	0	TAAAAGCTGCAAGAGACTCA
395208	5-10-5	139	741	760	0	TCAGAGAAAACAGTCACCGA
							399833	5-10-5	92	871	890	0	AGAGACAGGAAGCTGCAGCT
395209	5-10-5	142	878	897	0	TCATTTTAGAGACAGGAAGC
							395210	5-10-5	113	915	934	0	GAATAACAGTGATGTCTGGC
395211	5-10-5	138	968	987	0	TCACAGCTCACCGAGTCTGC
							395212	5-10-5	98	998	1017	0	AGTGTAAAATAAAGCCCCTA
395213	5-10-5	96	1075	1094	0	AGGACCCAAGTCATCCTGCT
							395214	5-10-5	124	1105	1124	0	GGCCATCAGCTGGCAATGCT
399834	5-10-5	82	1144	1163	0	AAGGAAAGGGAGGCCTAGAG
							395215	5-10-5	133	1149	1168	0	TAGACAAGGAAAGGGAGGCC
395216	5-10-5	103	1155	1174	0	ATTTCATAGACAAGGAAAGG
							395217	5-10-5	155	1275	1294	0	CTTATAGTTAACACACAGAA
399835	5-10-5	156	1283	1302	0	AAGTCAACCTTATAGTTAAC
							395218	5-10-5	146	1315	1334	0	TGACATTTGTGGGAGAGGAG
395219	5-10-5	161	1322	1341	0	TCCAAGGTGACATTTGTGGG
							395160	5-10-5	19	1365	1384	0	CTGGTGTCTAGGAGATACAC
399797	5-10-5	20	1370	1389	0	GTATGCTGGTGTCTAGGAGA
							395161	5-10-5	21	1390	1409	0	GATTTCCCGGTGGTCACTCT
399798	5-10-5	22	1396	1415	0	GCCCTCGATTTCCCGGTGGT
							399799	5-10-5	23	1410	1429	0	GTGACCATGACCCTGCCCTC
395162	5-10-5	24	1420	1439	0	CTCGAAGTCGGTGACCATGA
							395163	5-10-5	25	1453	1472	0	GTGGAAGCGGGTCCCGTCCT
395164	5-10-5	26	1500	1519	0	ACCCCTGCCAGGTGGGTGCC
							399800	5-10-5	27	1505	1524	0	TGACCACCCCTGCCAGGTGG
395165	5-10-5	28	1534	1553	0	ACCCTTGGCCACGCCGGCAT
							395166	5-10-5	29	1570	1589	0	TTGGCAGTTGAGCACGCGCA
399801	5-10-5	30	1575	1594	0	TTCCCTTGGCAGTTGAGCAC
							395167	5-10-5	31	1607	1626	0	CCAGGCCTATGAGGGTGCCG
395168	5-10-5	32	1628	1647	0	GCTGGCTTTTCCGAATAAAC
							395169	5-10-5	33	1740	1759	0	GTGACCAGCACGACCCCAGC
395175	5-10-5	39	1822	1841	0	TGGAGGCACCAATGATGTCC
							399804	5-10-5	40	1833	1852	0	GCTGCAGTCGCTGGAGGCAC
399805	5-10-5	41	1844	1863	0	ACAAAGCAGGTGCTGCAGTC
							395176	5-10-5	101	1898	1917	0	ATGGCTGCAATGCCAGCCAC
399806	5-10-5	42	1903	1922	0	GCATCATGGCTGCAATGCCA
							399807	5-10-5	43	1911	1930	0	GGCAGACAGCATCATGGCTG
399808	5-10-5	44	1959	1978	0	GAAGTGGATCAGTCTCTGCC
							395177	5-10-5	45	1967	1986	0	TTGGCAGAGAAGTGGATCAG
399809	5-10-5	46	1972	1991	0	CATCTTTGGCAGAGAAGTGG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							399810	5-10-5	47	1978	1997	0	TGATGACATCTTTGGCAGAG
399811	5-10-5	48	1985	2004	0	GCCTCATTGATGACATCTTT
							399812	5-10-5	49	1997	2016	0	TCAGGGAACCAGGCCTCATT
395178	5-10-5	50	2002	2021	0	GGTCCTCAGGGAACCAGGCC
							395179	5-10-5	87	2009	2028	0	ACCCGCTGGTCCTCAGGGAA
399813	5-10-5	51	2016	2035	0	GGTCAGTACCCGCTGGTCCT
							395180	5-10-5	119	2038	2057	0	GCAGGGCGGCCACCAGGTTG
395181	5-10-5	52	2073	2092	0	AAACAGCTGCCAACCTGCCC
							399814	5-10-5	53	2078	2097	0	CTGCAAAACAGCTGCCAACC
395220	5-10-5	104	2085	2104	0	CACAGTCCTGCAAAACAGCT
							399836	5-10-5	130	2095	2114	0	GTGCTGACCACACAGTCCTG
395182	5-10-5	54	2108	2127	0	GTAGGCCCCGAGTGTGCTGA
							399815	5-10-5	55	2173	2192	0	AGAAACTGGAGCAGCTCAGC
399816	5-10-5	56	2179	2198	0	TCCTGGAGAAACTGGAGCAG
							395186	5-10-5	60	2355	2374	0	CTTTGCATTCCAGACCTGGG
399817	5-10-5	61	2360	2379	0	CTTGACTTTGCATTCCAGAC
							395187	5-10-5	62	2565	2584	0	GGCAGCAGATGGCAACGGCT
395188	5-10-5	154	2665	2684	0	TTTTAAAGCTCAGCCCCAGC
							399818	5-10-5	63	2670	2689	0	AACCATTTTAAAGCTCAGCC
395189	5-10-5	64	2759	2778	0	TCAAGGGCCAGGCCAGCAGC
							399819	5-10-5	65	2764	2783	0	CCCACTCAAGGGCCAGGCCA
399820	5-10-5	122	2837	2856	0	GGAGGGAGCTTCCTGGCACC
							395190	5-10-5	66	2852	2871	0	ATGCCCCACAGTGAGGGAGG
395191	5-10-5	67	2861	2880	0	AATGGTGAAATGCCCCACAG
							395192	5-10-5	153	2904	2923	0	TTGGGAGCAGCTGGCAGCAC
395193	5-10-5	68	3005	3024	0	CATGGGAAGAATCCTGCCTC
							395194	5-10-5	69	3087	3106	0	GGAGATGAGGGCCATCAGCA
395195	5-10-5	70	3155	3174	0	TAGATGCCATCCAGAAAGCT
							399821	5-10-5	71	3161	3180	0	TCTGGCTAGATGCCATCCAG
395196	5-10-5	72	3238	3257	0	GGCATAGAGCAGAGTAAAGG
							399822	5-10-5	73	3243	3262	0	AGCCTGGCATAGAGCAGAGT
399823	5-10-5	135	3249	3268	0	TAGCACAGCCTGGCATAGAG
							395197	5-10-5	112	3482	3501	0	GAAGAGGCTTGGCTTCAGAG
399824	5-10-5	74	3488	3507	0	AAGTAAGAAGAGGCTTGGCT
							395198	5-10-5	75	3692	3711	0	GCTCAAGGAGGGACAGTTGT
395199	5-10-5	76	3727	3746	0	AAAGATAAATGTCTGCTTGC
							399825	5-10-5	77	3732	3751	0	ACCCAAAAGATAAATGTCTG
395200	5-10-5	78	3798	3817	0	TCTTCAAGTTACAAAAGCAA
							399826	5-10-5	99	3805	3824	0	ATAAATATCTTCAAGTTACA
405869	5-10-5	218	1392	1411	0	TCGATTTCCCGGTGGTCACT
							405870	5-10-5	219	1393	1412	0	CTCGATTTCCCGGTGGTCAC
405871	5-10-5	220	1394	1413	0	CCTCGATTTCCCGGTGGTCA
							405872	5-10-5	221	1395	1414	0	CCCTCGATTTCCCGGTGGTC
405873	5-10-5	222	1397	1416	0	TGCCCTCGATTTCCCGGTGG
							405874	5-10-5	223	1398	1417	0	CTGCCCTCGATTTCCCGGTG
405875	5-10-5	224	1399	1418	0	CCTGCCCTCGATTTCCCGGT

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							405876	5-10-5	225	1400	1419	0	CCCTGCCCTCGATTTCCCGG
405877	5-10-5	246	1530	1549	0	TTGGCCACGCCGGCATCCCG
							405878	5-10-5	247	1531	1550	0	CTTGGCCACGCCGGCATCCC
405879	5-10-5	248	1532	1551	0	CCTTGGCCACGCCGGCATCC
							405880	5-10-5	249	1533	1552	0	CCCTTGGCCACGCCGGCATC
405881	5-10-5	250	1535	1554	0	CACCCTTGGCCACGCCGGCA
							405882	5-10-5	251	1536	1555	0	GCACCCTTGGCCACGCCGGC
405883	5-10-5	252	1537	1556	0	GGCACCCTTGGCCACGCCGG
							405884	5-10-5	253	1538	1557	0	TGGCACCCTTGGCCACGCCG
405885	5-10-5	346	1993	2012	0	GGAACCAGGCCTCATTGATG
							405886	5-10-5	347	1994	2013	0	GGGAACCAGGCCTCATTGAT
405887	5-10-5	348	1995	2014	0	AGGGAACCAGGCCTCATTGA
							405888	5-10-5	349	1996	2015	0	CAGGGAACCAGGCCTCATTG
405889	5-10-5	350	1998	2017	0	CTCAGGGAACCAGGCCTCAT
							405890	5-10-5	351	1999	2018	0	CCTCAGGGAACCAGGCCTCA
405891	5-10-5	352	2000	2019	0	TCCTCAGGGAACCAGGCCTC
							405892	5-10-5	353	2001	2020	0	GTCCTCAGGGAACCAGGCCT
405893	5-10-5	431	3083	3102	0	ATGAGGGCCATCAGCACCTT
							405894	5-10-5	432	3084	3103	0	GATGAGGGCCATCAGCACCT
405895	5-10-5	433	3085	3104	0	AGATGAGGGCCATCAGCACC
							405896	5-10-5	434	3086	3105	0	GAGATGAGGGCCATCAGCAC
405897	5-10-5	435	3088	3107	0	TGGAGATGAGGGCCATCAGC
							405898	5-10-5	436	3089	3108	0	CTGGAGATGAGGGCCATCAG
405899	5-10-5	437	3090	3109	0	GCTGGAGATGAGGGCCATCA
							405900	5-10-5	438	3091	3110	0	AGCTGGAGATGAGGGCCATC
405901	5-10-5	439	3157	3176	0	GCTAGATGCCATCCAGAAAG
							405902	5-10-5	440	3158	3177	0	GGCTAGATGCCATCCAGAAA
405903	5-10-5	441	3159	3178	0	TGGCTAGATGCCATCCAGAA
							405904	5-10-5	442	3160	3179	0	CTGGCTAGATGCCATCCAGA
405905	5-10-5	443	3162	3181	0	CTCTGGCTAGATGCCATCCA
							405906	5-10-5	444	3163	3182	0	CCTCTGGCTAGATGCCATCC
405907	5-10-5	445	3164	3183	0	GCCTCTGGCTAGATGCCATC
							405908	5-10-5	446	3165	3184	0	AGCCTCTGGCTAGATGCCAT
405909	5-10-5	267	1630	1649	0	CAGCTGGCTTTTCCGAATAA
							405910	5-10-5	268	1632	1651	0	ACCAGCTGGCTTTTCCGAAT
405911	5-10-5	269	1634	1653	0	GGACCAGCTGGCTTTTCCGA
							405912	5-10-5	270	1638	1657	0	GGCTGGACCAGCTGGCTTTT
405913	5-10-5	275	1742	1761	0	CGGTGACCAGCACGACCCCA
							405914	5-10-5	276	1744	1763	0	AGCGGTGACCAGCACGACCC
405915	5-10-5	277	1746	1765	0	GCAGCGGTGACCAGCACGAC
							405916	5-10-5	278	1748	1767	0	CGGCAGCGGTGACCAGCACG
405917	5-10-5	280	1752	1771	0	TTGCCGGCAGCGGTGACCAG
							405918	5-10-5	281	1754	1773	0	AGTTGCCGGCAGCGGTGACC
405919	5-10-5	282	1756	1775	0	GAAGTTGCCGGCAGCGGTGA
							405920	5-10-5	283	1758	1777	0	CGGAAGTTGCCGGCAGCGGT
405921	5-10-5	284	1760	1779	0	CCCGGAAGTTGCCGGCAGCG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							405922	5-10-5	285	1762	1781	0	GTCCCGGAAGTTGCCGGCAG
405937	5-10-5	306	1820	1839	0	GAGGCACCAATGATGTCCTC
							405938	5-10-5	307	1824	1843	0	GCTGGAGGCACCAATGATGT
405939	5-10-5	308	1826	1845	0	TCGCTGGAGGCACCAATGAT
							405940	5-10-5	309	1828	1847	0	AGTCGCTGGAGGCACCAATG
405941	5-10-5	310	1830	1849	0	GCAGTCGCTGGAGGCACCAA
							405942	5-10-5	311	1835	1854	0	GTGCTGCAGTCGCTGGAGGC
405943	5-10-5	312	1837	1856	0	AGGTGCTGCAGTCGCTGGAG
							405944	5-10-5	314	1840	1859	0	AGCAGGTGCTGCAGTCGCTG
405945	5-10-5	315	1842	1861	0	AAAGCAGGTGCTGCAGTCGC
							405946	5-10-5	316	1846	1865	0	ACACAAAGCAGGTGCTGCAG
405947	5-10-5	317	1848	1867	0	TGACACAAAGCAGGTGCTGC
							405948	5-10-5	319	1900	1919	0	TCATGGCTGCAATGCCAGCC
405949	5-10-5	320	1905	1924	0	CAGCATCATGGCTGCAATGC
							405950	5-10-5	321	1907	1926	0	GACAGCATCATGGCTGCAAT
405951	5-10-5	322	1909	1928	0	CAGACAGCATCATGGCTGCA
							405952	5-10-5	323	1913	1932	0	TCGGCAGACAGCATCATGGC
405953	5-10-5	325	1917	1936	0	CGGCTCGGCAGACAGCATCA
							405954	5-10-5	326	1919	1938	0	TCCGGCTCGGCAGACAGCAT
405955	5-10-5	328	1946	1965	0	CTCTGCCTCAACTCGGCCAG
							405956	5-10-5	329	1948	1967	0	GTCTCTGCCTCAACTCGGCC
405957	5-10-5	330	1950	1969	0	CAGTCTCTGCCTCAACTCGG
							405958	5-10-5	331	1952	1971	0	ATCAGTCTCTGCCTCAACTC
405959	5-10-5	332	1954	1973	0	GGATCAGTCTCTGCCTCAAC
							405960	5-10-5	333	1956	1975	0	GTGGATCAGTCTCTGCCTCA
405961	5-10-5	334	1958	1977	0	AAGTGGATCAGTCTCTGCCT
							405962	5-10-5	335	1961	1980	0	GAGAAGTGGATCAGTCTCTG
405963	5-10-5	337	1965	1984	0	GGCAGAGAAGTGGATCAGTC
							405964	5-10-5	338	1969	1988	0	CTTTGGCAGAGAAGTGGATC
405965	5-10-5	339	1974	1993	0	GACATCTTTGGCAGAGAAGT
							405966	5-10-5	340	1976	1995	0	ATGACATCTTTGGCAGAGAA
405967	5-10-5	341	1980	1999	0	ATTGATGACATCTTTGGCAG
							405968	5-10-5	342	1982	2001	0	TCATTGATGACATCTTTGGC
405969	5-10-5	343	1987	2006	0	AGGCCTCATTGATGACATCT
							405970	5-10-5	344	1989	2008	0	CCAGGCCTCATTGATGACAT
405971	5-10-5	355	2004	2023	0	CTGGTCCTCAGGGAACCAGG
							405972	5-10-5	357	2006	2025	0	CGCTGGTCCTCAGGGAACCA
405973	5-10-5	358	2011	2030	0	GTACCCGCTGGTCCTCAGGG
							405974	5-10-5	359	2013	2032	0	CAGTACCCGCTGGTCCTCAG
405975	5-10-5	361	2075	2094	0	CAAAACAGCTGCCAACCTGC
							405976	5-10-5	362	2080	2099	0	TCCTGCAAAACAGCTGCCAA
405977	5-10-5	363	2082	2101	0	AGTCCTGCAAAACAGCTGCC
							405978	5-10-5	365	2105	2124	0	GGCCCCGAGTGTGCTGACCA
405979	5-10-5	366	2110	2129	0	GTGTAGGCCCCGAGTGTGCT
							405980	5-10-5	367	2112	2131	0	CCGTGTAGGCCCCGAGTGTG
405981	5-10-5	368	2114	2133	0	ATCCGTGTAGGCCCCGAGTG

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							405982	5-10-5	370	2118	2137	0	GGCCATCCGTGTAGGCCCCG
405983	5-10-5	371	2120	2139	0	GTGGCCATCCGTGTAGGCCC
							405984	5-10-5	372	2168	2187	0	CTGGAGCAGCTCAGCAGCTC
405985	5-10-5	373	2170	2189	0	AACTGGAGCAGCTCAGCAGC
							405986	5-10-5	374	2175	2194	0	GGAGAAACTGGAGCAGCTCA
405987	5-10-5	375	2177	2196	0	CTGGAGAAACTGGAGCAGCT
							405996	5-10-5	412	2357	2376	0	GACTTTGCATTCCAGACCTG
405997	5-10-5	415	2362	2381	0	TCCTTGACTTTGCATTCCAG
							405998	5-10-5	426	2568	2587	0	TCCGGCAGCAGATGGCAACG
406025	5-10-5	216	1362	1381	0	GTGTCTAGGAGATACACCTC
							406026	5-10-5	217	1367	1386	0	TGCTGGTGTCTAGGAGATAC
406027	5-10-5	226	1404	1423	0	ATGACCCTGCCCTCGATTTC
							406028	5-10-5	227	1406	1425	0	CCATGACCCTGCCCTCGATT
406029	5-10-5	228	1408	1427	0	GACCATGACCCTGCCCTCGA
							406030	5-10-5	229	1412	1431	0	CGGTGACCATGACCCTGCCC
406031	5-10-5	230	1414	1433	0	GTCGGTGACCATGACCCTGC
							406032	5-10-5	232	1418	1437	0	CGAAGTCGGTGACCATGACC
406033	5-10-5	237	1497	1516	0	CCTGCCAGGTGGGTGCCATG
							406034	5-10-5	238	1502	1521	0	CCACCCCTGCCAGGTGGGTG
406035	5-10-5	239	1507	1526	0	GCTGACCACCCCTGCCAGGT
							406036	5-10-5	241	1519	1538	0	GGCATCCCGGCCGCTGACCA
406037	5-10-5	242	1522	1541	0	GCCGGCATCCCGGCCGCTGA
							406038	5-10-5	245	1529	1548	0	TGGCCACGCCGGCATCCCGG
406039	5-10-5	257	1566	1585	0	CAGTTGAGCACGCGCAGGCT
							406040	5-10-5	258	1568	1587	0	GGCAGTTGAGCACGCGCAGG
406041	5-10-5	259	1572	1591	0	CCTTGGCAGTTGAGCACGCG
							406042	5-10-5	260	1577	1596	0	CCTTCCCTTGGCAGTTGAGC
406043	5-10-5	261	1581	1600	0	GTGCCCTTCCCTTGGCAGTT
							406044	5-10-5	262	1583	1602	0	CCGTGCCCTTCCCTTGGCAG
406045	5-10-5	266	1626	1645	0	TGGCTTTTCCGAATAAACTC
							408642	5-10-5	264	1606	1625	0	CAGGCCTATGAGGGTGCCGC
408653	5-10-5	354	2003	2022	0	TGGTCCTCAGGGAACCAGGC
							409126	5-10-5	447	1534	1553	1	ACCCTTGGTCACGCCGGCAT
410536	5-10-5	243	1527	1546	0	GCCACGCCGGCATCCCGGCC
							410537	5-10-5	244	1528	1547	0	GGCCACGCCGGCATCCCGGC
410538	5-10-5	254	1539	1558	0	CTGGCACCCTTGGCCACGCC
							410539	5-10-5	255	1540	1559	0	GCTGGCACCCTTGGCCACGC
410540	5-10-5	356	2005	2024	0	GCTGGTCCTCAGGGAACCAG
							410562	5-10-5	411	2356	2375	0	ACTTTGCATTCCAGACCTGG
410563	5-10-5	413	2358	2377	0	TGACTTTGCATTCCAGACCT
							410564	5-10-5	414	2359	2378	0	TTGACTTTGCATTCCAGACC
410565	5-10-5	419	2560	2579	0	CAGATGGCAACGGCTGTCAC
							410566	5-10-5	420	2561	2580	0	GCAGATGGCAACGGCTGTCA
410567	5-10-5	421	2562	2581	0	AGCAGATGGCAACGGCTGTC
							410568	5-10-5	422	2563	2582	0	CAGCAGATGGCAACGGCTGT
410569	5-10-5	423	2564	2583	0	GCAGCAGATGGCAACGGCTG

Isis number	Motif	SEQID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							410570	5-10-5	424	2566	2585	0	CGGCAGCAGATGGCAACGGC
410571	5-10-5	425	2567	2586	0	CCGGCAGCAGATGGCAACGG
							410572	5-10-5	427	2569	2588	0	CTCCGGCAGCAGATGGCAAC
410573	5-10-5	428	2570	2589	0	GCTCCGGCAGCAGATGGCAA
							410733	5-10-5	231	1416	1435	0	AAGTCGGTGACCATGACCCT
410734	5-10-5	279	1749	1768	0	CCGGCAGCGGTGACCAGCAC
							410737	5-10-5	313	1839	1858	0	GCAGGTGCTGCAGTCGCTGG
410738	5-10-5	324	1915	1934	0	GCTCGGCAGACAGCATCATG
							410739	5-10-5	336	1963	1982	0	CAGAGAAGTGGATCAGTCTC
410740	5-10-5	345	1991	2010	0	AACCAGGCCTCATTGATGAC
							410741	5-10-5	369	2116	2135	0	CCATCCGTGTAGGCCCCGAG
410753	5-10-5	215	1351	1370	0	ATACACCTCCACCAGGCTGC
							410754	5-10-5	233	1428	1447	0	GGCACATTCTCGAAGTCGGT
410755	5-10-5	234	1463	1482	0	TGGCCTGTCTGTGGAAGCGG
							410756	5-10-5	235	1490	1509	0	GGTGGGTGCCATGACTGTCA
410757	5-10-5	240	1515	1534	0	TCCCGGCCGCTGACCACCCC
							410758	5-10-5	256	1545	1564	0	CGCATGCTGGCACCCTTGGC
410759	5-10-5	263	1594	1613	0	GGTGCCGCTAACCGTGCCCT
							410760	5-10-5	265	1618	1637	0	CCGAATAAACTCCAGGCCTA
410761	5-10-5	271	1649	1668	0	GTGGCCCCACAGGCTGGACC
							410762	5-10-5	272	1662	1681	0	AGCAGCACCACCAGTGGCCC
410763	5-10-5	273	1684	1703	0	GCTGTACCCACCCGCCAGGG
							410764	5-10-5	274	1730	1749	0	CGACCCCAGCCCTCGCCAGG
410769	5-10-5	318	1858	1877	0	TCCCACTCTGTGACACAAAG
							410770	5-10-5	327	1933	1952	0	CGGCCAGGGTGAGCTCCGGC
410771	5-10-5	360	2061	2080	0	ACCTGCCCCATGGGTGCTGG
							410776	5-10-5	408	2245	2264	0	GTGCCAAGGTCCTCCACCTC
410777	5-10-5	409	2265	2284	0	TCAGCACAGGCGGCTTGTGG
							410778	5-10-5	410	2295	2314	0	CCACGCACTGGTTGGGCTGA
410779	5-10-5	416	2375	2394	0	CGGGATTCCATGCTCCTTGA
							410780	5-10-5	417	2405	2424	0	GCAGGCCACGGTCACCTGCT
410781	5-10-5	418	2442	2461	0	GGAGGGCACTGCAGCCAGTC
							410782	5-10-5	429	2580	2599	0	CCAGGTGCCGGCTCCGGCAG
410783	5-10-5	430	2590	2609	0	GAGGCCTGCGCCAGGTGCCG

In certain embodiments, the antisense chemical combination target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:3 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the motif that the 3-14-3 breach is widened in the table 11.Table 13 illustration the antisense compounds widened of the breach of target SEQ ID NO:3, it has the 3-14-3 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 13: the breach polymers antisense compounds of target SEQ ID NO:3 with 3-14-3 motif

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							399923	3-14-3	85	155	174	0	ACAAATTCCCAGACTCAGCA
399983	3-14-3	100	220	239	0	ATCTCAGGACAGGTGAGCAA
							399984	3-14-3	116	234	253	0	GAGTAGAGATTCTCATCTCA
399924	3-14-3	129	290	309	0	GTGCCATCTGAACAGCACCT
							399985	3-14-3	117	302	321	0	GAGTCTTCTGAAGTGCCATC
399986	3-14-3	81	377	396	0	AAGCAGGGCCTCAGGTGGAA
							399925	3-14-3	110	400	419	0	CCTGGAACCCCTGCAGCCAG
399926	3-14-3	152	451	470	0	TTCAGGCAGGTTGCTGCTAG
							399987	3-14-3	83	460	479	0	AAGGAAGACTTCAGGCAGGT
399927	3-14-3	140	472	491	0	TCAGCCAGGCCAAAGGAAGA
							399988	3-14-3	137	586	605	0	TAGGGAGAGCTCACAGATGC
399928	3-14-3	136	596	615	0	TAGGAGAAAGTAGGGAGAGC
							399929	3-14-3	132	653	672	0	TAAAAGCTGCAAGAGACTCA
399930	3-14-3	139	741	760	0	TCAGAGAAAACAGTCACCGA
							399989	3-14-3	92	871	890	0	AGAGACAGGAAGCTGCAGCT
399931	3-14-3	142	878	897	0	TCATTTTAGAGACAGGAAGC
							399932	3-14-3	113	915	934	0	GAATAACAGTGATGTCTGGC
399933	3-14-3	138	968	987	0	TCACAGCTCACCGAGTCTGC
							399934	3-14-3	98	998	1017	0	AGTGTAAAATAAAGCCCCTA
399935	3-14-3	96	1075	1094	0	AGGACCCAAGTCATCCTGCT
							399936	3-14-3	124	1105	1124	0	GGCCATCAGCTGGCAATGCT
399990	3-14-3	82	1144	1163	0	AAGGAAAGGGAGGCCTAGAG
							399937	3-14-3	133	1149	1168	0	TAGACAAGGAAAGGGAGGCC
399938	3-14-3	103	1155	1174	0	ATTTCATAGACAAGGAAAGG
							399939	3-14-3	155	1275	1294	0	CTTATAGTTAACACACAGAA
399991	3-14-3	156	1283	1302	0	AAGTCAACCTTATAGTTAAC
							399940	3-14-3	146	1315	1334	0	TGACATTTGTGGGAGAGGAG
399941	3-14-3	161	1322	1341	0	TCCAAGGTGACATTTGTGGG
							399882	3-14-3	19	1365	1384	0	CTGGTGTCTAGGAGATACAC
399953	3-14-3	20	1370	1389	0	GTATGCTGGTGTCTAGGAGA
							399883	3-14-3	21	1390	1409	0	GATTTCCCGGTGGTCACTCT
399954	3-14-3	22	1396	1415	0	GCCCTCGATTTCCCGGTGGT
							399955	3-14-3	23	1410	1429	0	GTGACCATGACCCTGCCCTC
399884	3-14-3	24	1420	1439	0	CTCGAAGTCGGTGACCATGA
							399885	3-14-3	25	1453	1472	0	GTGGAAGCGGGTCCCGTCCT
399886	3-14-3	26	1500	1519	0	ACCCCTGCCAGGTGGGTGCC
							399956	3-14-3	27	1505	1524	0	TGACCACCCCTGCCAGGTGG
399887	3-14-3	28	1534	1553	0	ACCCTTGGCCACGCCGGCAT
							399888	3-14-3	29	1570	1589	0	TTGGCAGTTGAGCACGCGCA
399957	3-14-3	30	1575	1594	0	TTCCCTTGGCAGTTGAGCAC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							399889	3-14-3	31	1607	1626	0	CCAGGCCTATGAGGGTGCCG
399890	3-14-3	32	1628	1647	0	GCTGGCTTTTCCGAATAAAC
							399891	3-14-3	33	1740	1759	0	GTGACCAGCACGACCCCAGC
399897	3-14-3	39	1822	1841	0	TGGAGGCACCAATGATGTCC
							399960	3-14-3	40	1833	1852	0	GCTGCAGTCGCTGGAGGCAC
399961	3-14-3	41	1844	1863	0	ACAAAGCAGGTGCTGCAGTC
							399898	3-14-3	101	1898	1917	0	ATGGCTGCAATGCCAGCCAC
399962	3-14-3	42	1903	1922	0	GCATCATGGCTGCAATGCCA
							399963	3-14-3	43	1911	1930	0	GGCAGACAGCATCATGGCTG
399964	3-14-3	44	1959	1978	0	GAAGTGGATCAGTCTCTGCC
							399899	3-14-3	45	1967	1986	0	TTGGCAGAGAAGTGGATCAG
399965	3-14-3	46	1972	1991	0	CATCTTTGGCAGAGAAGTGG
							399966	3-14-3	47	1978	1997	0	TGATGACATCTTTGGCAGAG
399967	3-14-3	48	1985	2004	0	GCCTCATTGATGACATCTTT
							399968	3-14-3	49	1997	2016	0	TCAGGGAACCAGGCCTCATT
399900	3-14-3	50	2002	2021	0	GGTCCTCAGGGAACCAGGCC
							399901	3-14-3	87	2009	2028	0	ACCCGCTGGTCCTCAGGGAA
399969	3-14-3	51	2016	2035	0	GGTCAGTACCCGCTGGTCCT
							399902	3-14-3	119	2038	2057	0	GCAGGGCGGCCACCAGGTTG
399903	3-14-3	52	2073	2092	0	AAACAGCTGCCAACCTGCCC
							399970	3-14-3	53	2078	2097	0	CTGCAAAACAGCTGCCAACC
399942	3-14-3	104	2085	2104	0	CACAGTCCTGCAAAACAGCT
							399992	3-14-3	130	2095	2114	0	GTGCTGACCACACAGTCCTG
399904	3-14-3	54	2108	2127	0	GTAGGCCCCGAGTGTGCTGA
							399971	3-14-3	55	2173	2192	0	AGAAACTGGAGCAGCTCAGC
399972	3-14-3	56	2179	2198	0	TCCTGGAGAAACTGGAGCAG
							399908	3-14-3	60	2355	2374	0	CTTTGCATTCCAGACCTGGG
399973	3-14-3	61	2360	2379	0	CTTGACTTTGCATTCCAGAC
							399909	3-14-3	62	2565	2584	0	GGCAGCAGATGGCAACGGCT
399910	3-14-3	154	2665	2684	0	TTTTAAAGCTCAGCCCCAGC
							399974	3-14-3	63	2670	2689	0	AACCATTTTAAAGCTCAGCC
399911	3-14-3	64	2759	2778	0	TCAAGGGCCAGGCCAGCAGC
							399975	3-14-3	65	2764	2783	0	CCCACTCAAGGGCCAGGCCA
399976	3-14-3	122	2837	2856	0	GGAGGGAGCTTCCTGGCACC
							399912	3-14-3	66	2852	2871	0	ATGCCCCACAGTGAGGGAGG
399913	3-14-3	67	2861	2880	0	AATGGTGAAATGCCCCACAG
							399914	3-14-3	153	2904	2923	0	TTGGGAGCAGCTGGCAGCAC
399915	3-14-3	68	3005	3024	0	CATGGGAAGAATCCTGCCTC
							399916	3-14-3	69	3087	3106	0	GGAGATGAGGGCCATCAGCA
399917	3-14-3	70	3155	3174	0	TAGATGCCATCCAGAAAGCT
							399977	3-14-3	71	3161	3180	0	TCTGGCTAGATGCCATCCAG
399918	3-14-3	72	3238	3257	0	GGCATAGAGCAGAGTAAAGG
							399978	3-14-3	73	3243	3262	0	AGCCTGGCATAGAGCAGAGT
399979	3-14-3	135	3249	3268	0	TAGCACAGCCTGGCATAGAG
							399919	3-14-3	112	3482	3501	0	GAAGAGGCTTGGCTTCAGAG
399980	3-14-3	74	3488	3507	0	AAGTAAGAAGAGGCTTGGCT
							399920	3-14-3	75	3692	3711	0	GCTCAAGGAGGGACAGTTGT
399921	3-14-3	76	3727	3746	0	AAAGATAAATGTCTGCTTGC

Isis number	Motif	SEQ ID NO	5 ' target site on the SEQ ID NO:3	3 ' target site on the SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							399981	3-14-3	77	3732	3751	0	ACCCAAAAGATAAATGTCTG
399922	3-14-3	78	3798	3817	0	TCTTCAAGTTACAAAAGCAA
							399982	3-14-3	99	3805	3824	0	ATAAATATCTTCAAGTTACA
405604	3-14-3	236	1493	1512	0	CCAGGTGGGTGCCATGACTG
							405641	3-14-3	373	2170	2189	0	AACTGGAGCAGCTCAGCAGC
410583	3-14-3	243	1527	1546	0	GCCACGCCGGCATCCCGGCC
							410584	3-14-3	244	1528	1547	0	GGCCACGCCGGCATCCCGGC
410585	3-14-3	245	1529	1548	0	TGGCCACGCCGGCATCCCGG
							410586	3-14-3	246	1530	1549	0	TTGGCCACGCCGGCATCCCG
410587	3-14-3	247	1531	1550	0	CTTGGCCACGCCGGCATCCC
							410588	3-14-3	248	1532	1551	0	CCTTGGCCACGCCGGCATCC
410589	3-14-3	249	1533	1552	0	CCCTTGGCCACGCCGGCATC
							410590	3-14-3	250	1535	1554	0	CACCCTTGGCCACGCCGGCA
410591	3-14-3	251	1536	1555	0	GCACCCTTGGCCACGCCGGC
							410592	3-14-3	252	1537	1556	0	GGCACCCTTGGCCACGCCGG
410593	3-14-3	253	1538	1557	0	TGGCACCCTTGGCCACGCCG
							410594	3-14-3	254	1539	1558	0	CTGGCACCCTTGGCCACGCC
410595	3-14-3	255	1540	1559	0	GCTGGCACCCTTGGCCACGC
							410596	3-14-3	348	1995	2014	0	AGGGAACCAGGCCTCATTGA
410597	3-14-3	349	1996	2015	0	CAGGGAACCAGGCCTCATTG
							410598	3-14-3	350	1998	2017	0	CTCAGGGAACCAGGCCTCAT
410599	3-14-3	351	1999	2018	0	CCTCAGGGAACCAGGCCTCA
							410600	3-14-3	352	2000	2019	0	TCCTCAGGGAACCAGGCCTC
410601	3-14-3	353	2001	2020	0	GTCCTCAGGGAACCAGGCCT
							410602	3-14-3	354	2003	2022	0	TGGTCCTCAGGGAACCAGGC
410603	3-14-3	355	2004	2023	0	CTGGTCCTCAGGGAACCAGG
							410604	3-14-3	356	2005	2024	0	GCTGGTCCTCAGGGAACCAG
410633	3-14-3	411	2356	2375	0	ACTTTGCATTCCAGACCTGG
							410634	3-14-3	412	2357	2376	0	GACTTTGCATTCCAGACCTG
410635	3-14-3	413	2358	2377	0	TGACTTTGCATTCCAGACCT
							410636	3-14-3	414	2359	2378	0	TTGACTTTGCATTCCAGACC
410637	3-14-3	419	2560	2579	0	CAGATGGCAACGGCTGTCAC
							410638	3-14-3	420	2561	2580	0	GCAGATGGCAACGGCTGTCA
410639	3-14-3	421	2562	2581	0	AGCAGATGGCAACGGCTGTC
							410640	3-14-3	422	2563	2582	0	CAGCAGATGGCAACGGCTGT
410641	3-14-3	423	2564	2583	0	GCAGCAGATGGCAACGGCTG
							410642	3-14-3	424	2566	2585	0	CGGCAGCAGATGGCAACGGC
410643	3-14-3	425	2567	2586	0	CCGGCAGCAGATGGCAACGG
							410644	3-14-3	426	2568	2587	0	TCCGGCAGCAGATGGCAACG
410645	3-14-3	427	2569	2588	0	CTCCGGCAGCAGATGGCAAC
							410646	3-14-3	428	2570	2589	0	GCTCCGGCAGCAGATGGCAA

In certain embodiments, the antisense chemical combination target PCSK9 nucleic acid widened of breach.In some such embodiment, the antisense compounds target SEQ ID NO:3 that breach is widened.In some such embodiment, illustrative nucleotide sequence has the 2-13-5 breach and widens motif in the table 11.Table 14 illustration the antisense compounds widened of the breach of target SEQ ID NO:3, it has the 2-13-5 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 14: the breach polymers antisense compounds of target SEQ ID NO:3 with 2-13-5 motif

ISIS number	Motif	SEQ ID NO	5 ' initiation site to SEQ ID NO:3	3 ' initiation site to SEQ ID NO:3	Mispairing	Sequence (5 '-3 ')
							410658	2-13-5	243	1527	1546	0	GCCACGCCGGCATCCCGGCC
410659	2-13-5	244	1528	1547	0	GGCCACGCCGGCATCCCGGC
							410660	2-13-5	245	1529	1548	0	TGGCCACGCCGGCATCCCGG
410661	2-13-5	246	1530	1549	0	TTGGCCACGCCGGCATCCCG
							410662	2-13-5	247	1531	1550	0	CTTGGCCACGCCGGCATCCC
410663	2-13-5	248	1532	1551	0	CCTTGGCCACGCCGGCATCC
							410664	2-13-5	249	1533	1552	0	CCCTTGGCCACGCCGGCATC
410665	2-13-5	28	1534	1553	0	ACCCTTGGCCACGCCGGCAT
							410666	2-13-5	250	1535	1554	0	CACCCTTGGCCACGCCGGCA
410667	2-13-5	251	1536	1555	0	GCACCCTTGGCCACGCCGGC
							410668	2-13-5	252	1537	1556	0	GGCACCCTTGGCCACGCCGG
410669	2-13-5	253	1538	1557	0	TGGCACCCTTGGCCACGCCG
							410670	2-13-5	254	1539	1558	0	CTGGCACCCTTGGCCACGCC
410671	2-13-5	255	1540	1559	0	GCTGGCACCCTTGGCCACGC
							410672	2-13-5	348	1995	2014	0	AGGGAACCAGGCCTCATTGA
410673	2-13-5	349	1996	2015	0	CAGGGAACCAGGCCTCATTG
							410674	2-13-5	49	1997	2016	0	TCAGGGAACCAGGCCTCATT
410675	2-13-5	350	1998	2017	0	CTCAGGGAACCAGGCCTCAT
							410676	2-13-5	351	1999	2018	0	CCTCAGGGAACCAGGCCTCA
410677	2-13-5	352	2000	2019	0	TCCTCAGGGAACCAGGCCTC
							410678	2-13-5	353	2001	2020	0	GTCCTCAGGGAACCAGGCCT
410679	2-13-5	50	2002	2021	0	GGTCCTCAGGGAACCAGGCC
							410680	2-13-5	354	2003	2022	0	TGGTCCTCAGGGAACCAGGC
410681	2-13-5	355	2004	2023	0	CTGGTCCTCAGGGAACCAGG
							410682	2-13-5	356	2005	2024	0	GCTGGTCCTCAGGGAACCAG
410713	2-13-5	60	2355	2374	0	CTTTGCATTCCAGACCTGGG
							410714	2-13-5	411	2356	2375	0	ACTTTGCATTCCAGACCTGG
410715	2-13-5	412	2357	2376	0	GACTTTGCATTCCAGACCTG
							410716	2-13-5	413	2358	2377	0	TGACTTTGCATTCCAGACCT
410717	2-13-5	414	2359	2378	0	TTGACTTTGCATTCCAGACC
							410718	2-13-5	61	2360	2379	0	CTTGACTTTGCATTCCAGAC
410719	2-13-5	419	2560	2579	0	CAGATGGCAACGGCTGTCAC
							410720	2-13-5	420	2561	2580	0	GCAGATGGCAACGGCTGTCA
410721	2-13-5	421	2562	2581	0	AGCAGATGGCAACGGCTGTC
							410722	2-13-5	422	2563	2582	0	CAGCAGATGGCAACGGCTGT
410723	2-13-5	423	2564	2583	0	GCAGCAGATGGCAACGGCTG
							410724	2-13-5	62	2565	2584	0	GGCAGCAGATGGCAACGGCT
410725	2-13-5	424	2566	2585	0	CGGCAGCAGATGGCAACGGC
							410726	2-13-5	425	2567	2586	0	CCGGCAGCAGATGGCAACGG
410727	2-13-5	426	2568	2587	0	TCCGGCAGCAGATGGCAACG
							410728	2-13-5	427	2569	2588	0	CTCCGGCAGCAGATGGCAAC
410729	2-13-5	428	2570	2589	0	GCTCCGGCAGCAGATGGCAA

Following embodiment has been listed the target region of PCSK9 nucleic acid.The example of also having showed the antisense compounds of these target regions of target.It is any to connecting or examine the modification of base between sugared module, nucleosides to should be appreciated that the sequence of listing among each SEQ ID NO is independent of.Therefore, can comprise independently connecting or examine one or more modifications of base between sugared module, nucleosides by the defined antisense compounds of SEQ ID NO.Represent to examine the combination of base sequence and motif by the antisense compounds of Isis numbering (Isis number) description.

In certain embodiments, a zone of antisense compounds target PCSK9 nucleic acid.In certain embodiments, such compound contains one 8 Nucleotide core sequence at least jointly.In certain embodiments, the following Nucleotide zone of the targeting compounds SEQ ID NO:3 of so shared at least one 8 Nucleotide core sequence:

220-253,290-321,377-419,451-615,653-672,741-760,871-897,915-934,968-1017,1075-1124,1075-1174,1144-1174,1275-1302,1315-1341,1351-1389,1351-1447,1365-1439,1390-1417,1390-1429,1390-1439,1399-1425,1408-1435,1420-1447,1453-1482,1490-1516,1490-1564,1500-1526,1515-1541,1527-1553,1527-1554,1528-1554,1529-1555,1529-1556,1530-1556,1530-1557,1531-1557,1532-1558,1533-1559,1534-1559,1535-1559,1536-1559,1537-1564,1566-1602,1566-1681,1606-1626,1618-1645,1626-1653,1684-1703,1730-1781,1740-1767,1749-1775,1758-1781,1820-1847,1820-1877,1822-2198,1830-1856,1839-1865,1840-1867,1898-1924,1898-2035,1903-2127,1907-1934,1911-1938,1946-1971,1954-1980,1959-2035,1959-2057,1963-1988,1967-2035,1972-1999,1982-2008,1991-2018,1993-2019,1995-2022,1996-2023,1997-2024,1998-2025,1999-2025,2000-2025,2009-2035,2038-2139,2061-2139,2073-2099,2078-2104,2105-2131,2112-2139,2168-2198,2170-2177,2245-2284,2295-2394,2355-2381,2355-2394,2405-2461,2560-2587,2560-2609,2561-2588,2562-2589,2563-2589,2564-2589,2565-2589,2566-2589,2567-2589,2568-2589,2665-2689,2759-2783,2837-2880,2904-2923,3005-3024,3005-3174,3083-3110,3155-3184,3238-3268,3482-3711 or 3727-3751 or 3798-3824.

In certain embodiments, target region is the Nucleotide 290-321 of SEQ ID NO:3.In certain embodiments, the Nucleotide 290-321 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:117 or 129.In some such embodiment, the antisense compounds of the Nucleotide 290-321 of target SEQ ID NO:3 is selected from ISIS NO:395202,399924,399829 or 399985.

In certain embodiments, target region is the Nucleotide 220-253 of SEQ ID NO:3.In certain embodiments, the Nucleotide 220-253 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:100 or 116.In some such embodiment, the antisense compounds of the Nucleotide 220-253 of target SEQ ID NO:3 is selected from ISIS NO:399827,399983,399828 or 399984.

In certain embodiments, target region is the Nucleotide 377-419 of SEQ ID NO:3.In certain embodiments, the Nucleotide 377-419 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:81 or 110.In some such embodiment, the antisense compounds of the Nucleotide 377-419 of target SEQ ID NO:3 is selected from ISIS NO:399830,399986,395203 or 399925.

In certain embodiments, target region is the Nucleotide 451-615 of SEQ ID NO:3.In certain embodiments, the Nucleotide 451-615 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:152,140,137 or 136 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 451-615 of target SEQ ID NO:3 is selected from ISIS NO:395204,399926,399831,399987,395205,399927,399832,399988,395206 or 399928.

In certain embodiments, target region is the Nucleotide 653-672 of SEQ ID NO:3.In certain embodiments, the Nucleotide 653-672 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:132.In some such embodiment, the antisense compounds of the Nucleotide 653-672 of target SEQ ID NO:3 is selected from ISIS NO:395207 or 399929.

In certain embodiments, target region is the Nucleotide 741-760 of SEQ ID NO:3.In certain embodiments, the Nucleotide 741-760 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:139.In some such embodiment, the antisense compounds of the Nucleotide 741-760 of target SEQ ID NO:3 is selected from ISIS NO:395208 or 399930.

In certain embodiments, target region is the Nucleotide 871-897 of SEQ ID NO:3.In certain embodiments, the Nucleotide 871-897 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:92 or 142.In some such embodiment, the antisense compounds of the Nucleotide 871-897 of target SEQ ID NO:3 is selected from ISIS NO:399833,399989,395209 or 399931.

In certain embodiments, target region is the Nucleotide 915-934 of SEQ ID NO:3.In certain embodiments, the Nucleotide 915-934 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:113.In some such embodiment, the antisense compounds of the Nucleotide 915-934 of target SEQ ID NO:3 is selected from ISIS NO:395210 or 399932.

In certain embodiments, target region is the Nucleotide 968-1017 of SEQ ID NO:3.In certain embodiments, the Nucleotide 968-1017 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:98 or 138.In some such embodiment, the antisense compounds of the Nucleotide 968-1017 of target SEQ ID NO:3 is selected from ISIS NO:395211,399933,395212 or 399934.

In certain embodiments, target region is the Nucleotide 1075-1124 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1075-1124 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:96 or 124.In some such embodiment, the antisense compounds of the Nucleotide 1075-1124 of target SEQ ID NO:3 is selected from ISIS NO:395213,399935,395214 or 399936.

In certain embodiments, target region is the Nucleotide 1075-1174 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1075-1174 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:82,96,103,124 or 133 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1075-1174 of target SEQ ID NO:3 is selected from ISIS NO:395213,399935,395214,399936,399834,399990,395215,399937,395216 or 399938.

In certain embodiments, target region is the Nucleotide 1144-1174 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1144-1174 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:82,133 or 103 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1144-1174 of target SEQ ID NO:3 is selected from ISIS NO:399834,399990,395215,399937,395216 or 399938.

In certain embodiments, target region is the Nucleotide 1275-1302 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1275-1302 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:155 or 156.In some such embodiment, the antisense compounds of the Nucleotide 1275-1302 of target SEQ ID NO:3 is selected from ISIS NO:395217,399939,399835 or 399991.

In certain embodiments, target region is the Nucleotide 1315-1341 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1315-1341 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:146 or 161.In some such embodiment, the antisense compounds of the Nucleotide 1315-1341 of target SEQ ID NO:3 is selected from ISIS NO:395218,399940,395219 or 399941.

In certain embodiments, target region is the Nucleotide 1351-1389 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1351-1389 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:215,216,19,217 or 20 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1351-1389 of target SEQ ID NO:3 is selected from ISIS NO:410753,406025,395160,399882,406026,399797 or 399953.

In certain embodiments, target region is the Nucleotide 1351-1447 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1351-1447.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:215,216,19,217,20,21,218,219,220,221,22,222,223,224,225,226,227,228,23,229,230,231,232,24 or 233 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1351-1447 of target SEQID NO:3 is selected from ISIS NO:410753,406025,395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162,399884 or 410754.

In certain embodiments, target region is the Nucleotide 1365-1439 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1365-1439.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:19,20,21,22,23,24,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231 or 232 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1365-1439 of target SEQ ID NO:3 is selected from ISIS NO:395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162 or 399884.

In certain embodiments, target region is the Nucleotide 1390-1417 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1390-1417 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,218,219,220,221,22,222 or 223 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1390-1417 of target SEQID NO:3 is selected from ISIS NO:395161,399883,405869,405870,405871,405872,399798,399954,405873 or 405874.

In certain embodiments, target region is the Nucleotide 1390-1429 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1390-1429.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,217,218,219,220,221,222,223,224,225,226,227 or 228 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1390-1429 of target SEQ ID NO:3 is selected from ISIS NO:395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799 or 399955.

In certain embodiments, target region is the Nucleotide 1390-1439 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1390-1439.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:21,22,23,24,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231 or 232 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1390-1439 of target SEQ ID NO:3 is selected from ISIS NO:395160,399882,406026,399797,399953,395161,399883,405869,405870,405871,405872,399798,399954,405873,405874,405875,405876,406027,406028,406029,399799,399955,406030,406031,410733,406032,395162 or 399884.

In certain embodiments, target region is the Nucleotide 1399-1425 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1399-1425 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:224,225,226 or 227 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1399-1425 of target SEQ ID NO:3 is selected from ISIS NO:405875,405876,406027 or 406028.

In certain embodiments, target region is the Nucleotide 1408-1435 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1408-1435 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:228,23,229,230 or 231 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1408-1435 of target SEQ ID NO:3 is selected from ISIS NO:406029,399799,399955,406030,406031 or 410733.

In certain embodiments, target region is the Nucleotide 1420-1447 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1420-1447 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:24 or 233.In some such embodiment, the antisense compounds of the Nucleotide 1420-1447 of target SEQ ID NO:3 is selected from ISIS NO:395162,399884 or 410754.

In certain embodiments, target region is the Nucleotide 1453-1482 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1453-1482 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:25 or 234.In some such embodiment, the antisense compounds of the Nucleotide 1453-1482 of target SEQ ID NO:3 is selected from ISIS NO:395163,399885 or 410755.

In certain embodiments, target region is the Nucleotide 1490-1516 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1490-1516 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:235,236 or 237 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1490-1516 of target SEQ ID NO:3 is selected from ISIS NO:410756,405604 or 406033.

In certain embodiments, target region is the Nucleotide 1490-1564 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1490-1564.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:235,236,237,26,238,27,239,240,241,242,243,244,245,246,247,248,249,447,28,250,251,252,253,254,255 or 256 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1490-1564 of target SEQ ID NO:3 is selected from ISIS NO:410756,405604,406033,395164,399886,406034,399800,399956,406035,410757,406036,406037,410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589 or 410758.

In certain embodiments, target region is the Nucleotide 1500-1526 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1500-1526 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:26,238,27 or 239 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1500-1526 of target SEQ ID NO:3 is selected from ISIS NO:395164,399886,406034,399800,399956 or 406035.

In certain embodiments, target region is the Nucleotide 1515-1541 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1515-1541 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:240,241 or 242 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1515-1541 of target SEQ ID NO:3 is selected from ISIS NO:399886,406034,399800,399956 or 406035.

In certain embodiments, target region is the Nucleotide 1527-1553 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1527-1553.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:243,244,245,246,247,248,447,28 or 249 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1527-1553 of target SEQ IDNO:3 is selected from ISIS NO:410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887 or 410665.

In certain embodiments, target region is the Nucleotide 1527-1554 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1527-1554.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:243,244,245,246,247,248,249,447,28 or 250 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1527-1554 of target SEQID NO:3 is selected from ISIS NO:410536,410583,410658,410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,405881,410590,410666 or 410665.

In certain embodiments, target region is the Nucleotide 1528-1554 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1528-1554.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:244,245,246,247,248,249,447,28 or 250 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1528-1554 of target SEQ IDNO:3 is selected from ISIS NO:410537,410584,410659,406038,410585,410660,405877,410586,410661,405878,410587,410662,405879,410588,410663,405880,410589,410664,395165,399887,409126,410665 or 405881.

In certain embodiments, target region is the Nucleotide 1529-1555 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1529-1555.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:245,246,247,248,249,447,28,250 or 251 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1529-1555 of target SEQ IDNO:3 is selected from ISIS NO:406038,395165,399887,405877,405878,405879,405880,405881,405882,409126,410585,410586,410587,410588,410589,410590,410591,410660,410661,410662,410663,410664,410665,410666,410667 or 410667.

In certain embodiments, target region is the Nucleotide 1529-1556 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1529-1556.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:245,246,247,248,249,447,28,250,251 or 252 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1529-1556 of target SEQID NO:3 is selected from ISIS NO:406038,395165,399887,405877,405878,405879,405880,405881,405882,405883,409126,410585,410586,410587,410588,410589,410590,410591,410592,410660,410661,410662,410663,410664,410665,410666,410667 or 410668.

In certain embodiments, target region is the Nucleotide 1530-1556 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1530-1556.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:246,247,248,249,447,28,250,251 or 252 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1530-1556 of target SEQ IDNO:3 is selected from ISIS NO:406038,395165,399887,405877,405878,405879,405880,405881,405882,405883,409126,410585,410586,410587,410588,410589,410590,410591,410592,410660,410661,410662,410663,410664,410665,410666,410667,405884,410593,410669 or 410668.

In certain embodiments, target region is the Nucleotide 1530-1557 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1530-1557.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,246,247,248,249,250,251,252,253 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1530-1557 of target SEQ IDNO:3 is selected from ISIS NO:395165,399887,405877,405878,405879,405880,405881,405882,405883,405884,409126,410586,410587,410588,410589,410590,410591,410592,410593,410661,410662,410663,410664,410665,410666,410667,410668 or 410669.

In certain embodiments, target region is the Nucleotide 1531-1557 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1531-1557.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,247,248,249,250,251,252,253 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1531-1557 of target SEQ ID NO:3 is selected from ISIS NO:395165,399887,405878,405879,405880,405881,405882,405883,405884,409126,410587,410588,410589,410590,410591,410592,410593,410662,410663,410664,410665,410666,410667,410668 or 410669.

In certain embodiments, target region is the Nucleotide 1532-1558 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1532-1558.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,248,249,250,251,252,253,254 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1532-1558 of target SEQ ID NO:3 is selected from ISIS NO:405879,410588,410663,405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594 or 410670.

In certain embodiments, target region is the Nucleotide 1533-1559 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1533-1559 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,249,250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1533-1559 of target SEQ ID NO:3 is selected from ISIS NO:405880,410589,410664,395165,399887,410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1534-1559 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1534-1559 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:28,250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1534-1559 of target SEQ ID NO:3 is selected from ISIS NO:395165,399887,410665,405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670 or 410671.

In certain embodiments, target region is the Nucleotide 1535-1559 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1535-1559 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:250,251,252,253,254,255 or 447 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1535-1559 of target SEQ IDNO:3 is selected from ISIS NO:405881,410590,410666,405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594 or 410671.

In certain embodiments, target region is the Nucleotide 1536-1559 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1536-1559 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:251,252,253,254 or 255 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1536-1559 of target SEQ ID NO:3 is selected from ISIS NO:405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595 or 410671.

In certain embodiments, target region is the Nucleotide 1537-1564 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1537-1564 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:251,252,253,254,255 or 256 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1537-1564 of target SEQ ID NO:3 is selected from ISIS NO:405882,410591,410667,405883,410592,410668,405884,410593,410669,410538,410594,410670,410539,410595,410671 or 410758.

In certain embodiments, target region is the Nucleotide 1566-1602 of SEQ IDNO:3.In certain embodiments, antisense compounds targeted nucleotide 1566-1602.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:29,30,31,32,257,258,259,260,261 or 262 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1566-1602 of target SEQ IDNO:3 is selected from ISIS NO:395166,395167,395168,399801,399888,399889,399890,399957,405909,405910,405911,405912,406039,406040,406041,406042,406043 or 406044.

In certain embodiments, target region is the Nucleotide 1566-1681 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1566-1681 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:29,30,31,32,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271 or 272 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1566-1681 of target SEQ ID NO:3 is selected from ISIS NO:395166,395167,395168,399801,399888,399889,399890,399957,405909,405910,405911,405912,406039,406040,406041,406042,406043,406044,406045,408642,410759,410760,410761 or 410762.

In certain embodiments, target region is the Nucleotide 1606-1626 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1606-1626 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:264 or 31.In some such embodiment, the antisense compounds of the Nucleotide 1606-1626 of target SEQ ID NO:3 is selected from ISIS NO:408642,395167 or 399889.

In certain embodiments, target region is the Nucleotide 1618-1645 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1618-1645 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:265 or 266.In some such embodiment, the antisense compounds of the Nucleotide 1618-1645 of target SEQ ID NO:3 is selected from ISIS NO:410760 or 406045.

In certain embodiments, target region is the Nucleotide 1626-1653 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1626-1653 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:32,266,267,268 or 269 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1626-1653 of target SEQ ID NO:3 is selected from ISIS NO:395168,399890,405909,405910,405911 or 406045.

In certain embodiments, target region is the Nucleotide 1684-1703 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1684-1703 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:273.In some such embodiment, the antisense compounds of the Nucleotide 1684-1703 of target SEQ ID NO:3 is selected from ISIS NO:410763.

In certain embodiments, target region is the Nucleotide 1730-1781 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1730-1781 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,33,274,275,276,277,278,279,280,281,282,283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1730-1781 of target SEQ ID NO:3 is selected from ISIS NO:395169,399891,405913,405914,405915,405916,405917,405918,405919,405920,405921,405922,410734 or 410764.

In certain embodiments, target region is the Nucleotide 1740-1767 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1740-1767 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:33,275,276,277 or 278 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1740-1767 of target SEQ ID NO:3 is selected from ISIS NO:395169,399891,405913,405914,405915 or 405916.

In certain embodiments, target region is the Nucleotide 1749-1775 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1749-1775 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:279,280,281 or 282 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1749-1775 of target SEQ ID NO:3 is selected from ISIS NO:410734,405917,405918 or 405919.

In certain embodiments, target region is the Nucleotide 1758-1781 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1758-1781 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:283,284 or 285 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1758-1781 of target SEQ ID NO:3 is selected from ISIS NO:405920,405921 or 405922.

In certain embodiments, target region is the Nucleotide 1820-1847 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1820-1847 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:39,306,307,308 or 309 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1820-1847 of target SEQ ID NO:3 is selected from ISIS NO:395175,399897,405937,405938,405939 or 405940.

In certain embodiments, target region is the Nucleotide 1820-1877 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1820-1877 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:39,40,41,306,307,308,309,310,311,312,313,314,315,316,317 or 318 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1820-1877 of target SEQ ID NO:3 is selected from ISIS NO:395175,399804,399805,399897,399960,399961,405937,405938,405939,405940,405941,405942,405943,405944,405945,405946,405947,410737 or 410769.

In certain embodiments, target region is the Nucleotide 1822-2198 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1822-2198.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:39,307,308,309,310,40,311,312,313,314,315,41,41,316,317,318,101,319,42,320,321,322,43,323,324,325,326,327,328,329,330,331,332,333,334,44,335,336,337,45,338,46,339,340,47,341,342,48,343,344,345,346,347,3 or 366 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1822-2198 of target SEQ ID NO:3 is selected from ISIS NO:395175,399897,405938,405939,405940,405941,399804,399960,405942,405943,410737,405944,405945,399805,399961,405946,405947,410769,395176,399898,405948,399806,399962,405949,405950,405951,399807,399963,405952,410738,405953,405954 or 405979.

In certain embodiments, target region is the Nucleotide 1830-1856 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1830-1856 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:40,310,311 or 312 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1830-1856 of target SEQ ID NO:3 is selected from ISIS NO:399804,399960,405941,405942 or 405943.

In certain embodiments, target region is the Nucleotide 1839-1865 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1839-1865 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:41,313,314,315 or 316 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1839-1865 of target SEQ ID NO:3 is selected from ISIS NO:399805,399961,405944,405945,405946 or 410737.

In certain embodiments, target region is the Nucleotide 1840-1867 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1840-1867 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:314,315,316 or 317 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1840-1867 of target SEQ ID NO:3 is selected from ISIS NO:399961,405944,405945,405946,410737 or 405947.

In certain embodiments, target region is the Nucleotide 1898-1924 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1898-1924 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:42,101,319 or 320 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1898-1924 of target SEQ ID NO:3 is selected from ISIS NO:395176,399898,405948,399806,399962,405949 or 405949.

In certain embodiments, target region is the Nucleotide 1898-2035 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1898-2035 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:42,43,44,45,46,47,48,49,50,51,87,101,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1898-2035 of target SEQ ID NO:3 is selected from ISIS NO:395176,395177,395178,395179,399806,399807,399808,399809,399810,399811,399812,399813,399898,399899,399900,399901,399962,399963,399964,399965,399966,399967,399968,399969,405885,405886,405887,405888,405889,405890,405891,405892,405948,405949,405950,405951,405952,405953,405954,405955,405956,405957,405958,405959,405960,405961,405962,405963,405964,405965,405966,405967,405968,405969,405970,405971,405972,405973,405974,408653,410540,410596,410597,410598,410599,410600,410601,410602,410603,410604,410672,410673,410674,410675,410676,410677,410678,410679,410680,410681,410682,410738,410739,410740 or 410770.

In certain embodiments, target region is the Nucleotide 1903-2127 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1903-2127 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:42,320,321,322,43,323,324,325,326,327,328,329,330,331,332,333,334,44,335,336,337,45,338,46,339,340,47,341,342,48,343,344,345,346,347,348,349,49,350,351,352,353,50,354,355,356,357,87,358,359,51,119,360 or 54 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1903-2127 of target SEQ ID NO:3 is selected from ISISNO:399806,399962,405949,405950,405951,399807,399963,405952,410738,405953,405954,410770,405955,405956,405957,405958,405959,405960,405961,399808,399964,405962,410739,405963,395177,399899,405964,399809,399965,405965,405966,399810 or 399967.

In certain embodiments, target region is the Nucleotide 1907-1934 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1907-1934 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,321,322,323 or 324 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1907-1934 of target SEQ ID NO:3 is selected from ISIS NO:405950,405951,399807,399963,405952 or 410738.

In certain embodiments, target region is the Nucleotide 1911-1938 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1911-1938 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:43,323,324,325 or 326 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1911-1938 of target SEQ ID NO:3 is selected from ISIS NO:399807,399963,405952,410738,405953 or 405954.

In certain embodiments, target region is the Nucleotide 1946-1971 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1946-1971 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:328,329,330 or 331 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1946-1971 of target SEQ ID NO:3 is selected from ISIS NO:405955,405956,405957 or 405958.

In certain embodiments, target region is the Nucleotide 1954-1980 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1954-1980 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,332,333,334 or 335 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1954-1980 of target SEQ ID NO:3 is selected from ISIS NO:405959,405960,405961,399808,399964 or 405962.

In certain embodiments, target region is the Nucleotide 1959-2035 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1959-2035 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,335,336,337,45,338,46,339,340,47,341,342,48,343,344,345,346,347,348,349,49,350,351,352,353,50,354,355,356,357,87,358,359 or 51 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1959-2035 of target SEQ ID NO:3 is selected from ISIS NO:399808,399964,405962,410739,405963,395177,399899,405964,399809,399965,405965,405966,399810,399966,405967,405968,399811,399967,405969,405970,410740,405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674 or 399969.

In certain embodiments, target region is the Nucleotide 1959-2057 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1959-2057 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:44,335,336,337,45,338,46,339,340,47,341,342,48,343,344,345,346,347,348,349,49,350,351,352,353,50,354,355,356,357,87,358,359,51 or 119 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1959-2057 of target SEQ IDNO:3 is selected from ISIS NO:399808,399964,405962,410739,405963,395177,399899,405964,399809,399965,405965,405966,399810,399966,405967,405968,399811,399967,405969,405970,410740,405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674 or 399902.

In certain embodiments, target region is the Nucleotide 1963-1988 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1963-1988 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:45,336,337 or 338 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1963-1988 of target SEQ ID NO:3 is selected from ISIS NO:410739,405963,395177,399899 or 405964.

In certain embodiments, target region is the Nucleotide 1967-2035 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1967-2035 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:45,338,46,339,340,47,341,342,48,343,344,345,346,347,348,349,49,350,351,352,353,50,354,355,356,357,87,358,359 or 51 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1967-2035 of target SEQ ID NO:3 is selected from ISIS NO:395177,399899,405964,399809,399965,405965,405966,399810,399966,405967,405968,399811,399967,405969,405970,410740,405885,405886,405887,410596,410672,405888,410597,410673,399812,399968,410674,405889,410598,410675,405890,410599 or 399969.

In certain embodiments, target region is the Nucleotide 1972-1999 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1972-1999 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:46,47,339,340 or 341 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1972-1999 of target SEQ ID NO:3 is selected from ISIS NO:399809,399965,405965,405966,399810,399966 or 405967.

In certain embodiments, target region is the Nucleotide 1982-2008 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1982-2008 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:48,342,343 or 344 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1982-2008 of target SEQ ID NO:3 is selected from ISIS NO:405968,399811,399967,405969 or 405970.

In certain embodiments, target region is the Nucleotide 1991-2018 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1991-2018 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,345,346,347,348,349,350 or 351 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1991-2018 of target SEQ ID NO:3 is selected from ISIS NO:399812,399968,405885,405886,405887,405888,405889,405890,410596,410597,410598,410599,410672,410673,410674,410675,410676 or 410740.

In certain embodiments, target region is the Nucleotide 1993-2019 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1993-2019 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,346,347,348,349,350 or 354 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1993-2019 of target SEQ IDNO:3 is selected from ISIS NO:405885,405887,410596,410672,405888,410597,410673,399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600 or 410677.

In certain embodiments, target region is the Nucleotide 1995-2022 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 1995-2022.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:348,349,350,351,352,353,50 or 351.In some such embodiment, the antisense compounds of the Nucleotide 1995-2022 of target SEQ ID NO:3 is selected from ISIS NO:405887,410596,410672,405888,410597,410673,399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600,405892,410601,410678,395178,399900,410679,408653,410602 or 410680.

In certain embodiments, target region is the Nucleotide 1996-2023 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1996-2023 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,349,350,351,352,353,354 or 355 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1996-2023 of target SEQ ID NO:3 is selected from ISIS NO:395178,399812,399900,399968,405888,405889,405890,405891,405892,405971,408653,410597,410598,410599,410600,410601,410602,410603,410673,410674,410675,410676,410677,410678,410679,410680 or 410681.

In certain embodiments, target region is the Nucleotide 1997-2024 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1997-2024 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:49,50,350,351,352,353,354,355 or 356 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1997-2024 of target SEQ ID NO:3 is selected from ISIS NO:399812,399968,410674,405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,410679,408653,410602,410680,405971,410603,410681,410540,410604 or 410682.

In certain embodiments, target region is the Nucleotide 1998-2025 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1998-2025 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,350,351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1998-2025 of target SEQ ID NO:3 is selected from ISIS NO:405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region is the Nucleotide 1999-2025 of SEQ ID NO:3.In certain embodiments, the Nucleotide 1999-2025 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:50,351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 1999-2025 of target SEQ ID NO:3 is selected from ISIS NO:405889,410598,410675,405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region is the Nucleotide 2000-2025 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 2000-2025.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:351,352,353,354,355,356 or 357 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2000-2025 of target SEQ ID NO:3 is selected from ISIS NO:405890,410599,410676,405891,410600,410677,405892,410601,410678,395178,399900,410679,408653,410602,410680,405971,410603,410681,410540,410604,410682 or 405972.

In certain embodiments, target region is the Nucleotide 2009-2035 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2009-2035 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:51,87,358 or 359 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2009-2035 of target SEQ ID NO:3 is selected from ISIS NO:395179,399813,399901,399969,405973 or 405974.

In certain embodiments, target region is the Nucleotide 2038-2139 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2038-2139 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,54,104,119,130,360,361,362,363,365,366,367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2038-2139 of target SEQ ID NO:3 is selected from ISIS NO:395180,395181,395182,395220,399814,399836,399902,399903,399904,399942,399970,399992,405975,405976,405977,405978,405979,405980,405981,405982,405983,410741 or 410771.

In certain embodiments, target region is the Nucleotide 2061-2139 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 2061-2139.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,54,104,130,360,361,362,363,365,366,367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2061-2139 of target SEQ ID NO:3 is selected from ISIS NO:395181,395182,395220,399814,399836,399903,399904,399942,399970,399992,405975,405976,405977,405978,405979,405980,405981,405982,405983,410741 or 410771.

In certain embodiments, target region is the Nucleotide 2073-2099 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2073-2099 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:52,53,361 or 362 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2073-2099 of target SEQ ID NO:3 is selected from ISIS NO:395181,399814,399903,399970,405975 or 405976.

In certain embodiments, target region is the Nucleotide 2078-2104 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2078-2104 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:53,104,362 or 363 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2078-2104 of target SEQ ID NO:3 is selected from ISIS NO:395220,399814,399942,399970,405976 or 405977.

In certain embodiments, target region is the Nucleotide 2105-2131 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2105-2131 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:54,365,366 or 367 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2105-2131 of target SEQ ID NO:3 is selected from ISIS NO:395182,399904,405978,405979 or 405980.

In certain embodiments, target region is the Nucleotide 2112-2139 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2112-2139 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:367,368,369,370 or 371 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2112-2139 of target SEQ ID NO:3 is selected from ISIS NO:405980,405981,410741,405982 or 405983.

In certain embodiments, target region is the Nucleotide 2168-2198 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2168-2198 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,56,372,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2168-2198 of target SEQ ID NO:3 is selected from ISIS NO:399815,399816,399971,399972,405641,405984,405985,405986 or 405987.

In certain embodiments, target region is the Nucleotide 2170-2177 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2170-2177 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:55,373,374 or 375 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2170-2177 of target SEQ ID NO:3 is selected from ISIS NO:399815,399971,405641,405985,405986 or 405987.

In certain embodiments, target region is the Nucleotide 2245-2284 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2245-2284 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:408 or 409.In some such embodiment, the antisense compounds of the Nucleotide 2245-2284 of target SEQ ID NO:3 is selected from ISIS NO:410776 or 410777.

In certain embodiments, target region is the Nucleotide 2295-2394 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2295-2394 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,410,411,412,413,414,415 or 416 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2295-2394 of target SEQ ID NO:3 is selected from ISIS NO:395186,399817,399908,399973,405996,405997,410562,410563,410564,410633,410634,410635,410636,410713,410714,410715,410716,410717,410718,410778 or 410779.

In certain embodiments, target region is the Nucleotide 2355-2381 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2355-2381 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414 or 415 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2355-2381 of target SEQ IDNO:3 is selected from ISIS NO:395186,399817,399908,399973,405996,405997,410562,410563,410564,410633,410634,410635,410636,410713,410714,410715,410716,410717 or 410718.

In certain embodiments, target region is the Nucleotide 2355-2394 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2355-2394 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:60,61,411,412,413,414,415 or 416 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2355-2394 of target SEQ ID NO:3 is selected from ISIS NO:395186,399817,399908,399973,405996,405997,410562,410563,410564,410633,410634,410635,410636,410713,410714,410715,410716,410717,410718 or 410779.

In certain embodiments, target region is the Nucleotide 2405-2461 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2405-2461 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:417 or 418.In some such embodiment, the antisense compounds of the Nucleotide 2405-2461 of target SEQ ID NO:3 is selected from ISIS NO:410780 or 410781.

In certain embodiments, target region is the Nucleotide 2560-2587 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2560-2587 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425 or 426 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2560-2587 of target SEQ ID NO:3 is selected from ISIS NO:395187,399909,405998,410565,410566,410567,410568,410569,410570,410571,410637,410638,410639,410640,410641,410642,410643,410644,410719,410720,410721,410722,410723,410724,410725,410726 or 410727.

In certain embodiments, target region is the Nucleotide 2560-2609 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2560-2609 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,419,420,421,422,423,424,425,426,427,428,429 or 430 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2560-2609 of target SEQ ID NO:3 is selected from ISIS NO:395187,399909,405998,410565,410566,410567,410568,410569,410570,410571,410572,410573,410637,410638,410639,410640,410641,410642,410643,410644,410645,410646,410719,410720,410721,410722,410723,410724,410725,410726,410727,410728 or 410783.

In certain embodiments, target region is the Nucleotide 2561-2588 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 2561-2588.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:420,421,422,423,424,425,426,427 or 62 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2561-2588 of target SEQ IDNO:3 is selected from ISIS NO:410566,410638,410720,410567,410639,410721,410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405988,405998,410644,410727,410572,410645 or 410728.

In certain embodiments, target region is the Nucleotide 2562-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2562-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:62,421,422,423,424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2562-2589 of target SEQ ID NO:3 is selected from ISIS NO:395187,399909,405998,410567,410568,410569,410570,410571,410572,410573,410639,410640,410641,410642,410643,410644,410645,410646,410721,410722,410723,410724,410725,410726,410727,410728 or 410729.

In certain embodiments, target region is the Nucleotide 2563-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2563-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:422,423,424,425,426,427,428 or 62 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2563-2589 of target SEQID NO:3 is selected from ISIS NO:410568,410640,410722,410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2564-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2564-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:423,424,425,426,427,428 or 62 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2564-2589 of target SEQ IDNO:3 is selected from ISIS NO:410569,410641,410723,395187,399909,410724,410570,410642,410725,410571,410643,410726,405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2565-2589 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 2565-2589.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:424,425,426,427,428 or 62 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2565-2589 of target SEQ ID NO:3 is selected from ISIS NO:395187,399909,410724,410570,410642,410725,410571,410643,410726,405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2566-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2566-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:424,425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2566-2589 of target SEQ ID NO:3 is selected from ISIS NO:410570,410642,410725,410571,410643,410726,405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2567-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2567-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:425,426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2567-2589 of target SEQ ID NO:3 is selected from ISIS NO:410571,410643,410726,405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2568-2589 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2568-2589 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:426,427 or 428 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2568-2589 of target SEQ ID NO:3 is selected from ISIS NO:405988,405998,410644,410727,410572,410645,410728,410573,410646 or 410729.

In certain embodiments, target region is the Nucleotide 2665-2689 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2665-2689 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:63 or 154.In some such embodiment, the antisense compounds of the Nucleotide 2665-2689 of target SEQ ID NO:3 is selected from ISIS NO:395188,399910,399818 or 399974.

In certain embodiments, target region is the Nucleotide 2759-2783 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2759-2783 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:64 or 65.In some such embodiment, the antisense compounds of the Nucleotide 2759-2783 of target SEQ ID NO:3 is selected from ISIS NO:395189,399911,399819 or 399975.

In certain embodiments, target region is the Nucleotide 2837-2880 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2837-2880 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:66,67 or 122 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 2837-2880 of target SEQ ID NO:3 is selected from ISIS NO:399820,399976,395190,399912,395191 or 399913.

In certain embodiments, target region is the Nucleotide 2904-2923 of SEQ ID NO:3.In certain embodiments, the Nucleotide 2904-2923 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:153.In some such embodiment, the antisense compounds of the Nucleotide 2904-2923 of target SEQ ID NO:3 is selected from ISIS NO:395192 or 399914.

In certain embodiments, target region is the Nucleotide 3005-3024 of SEQ ID NO:3.In certain embodiments, the Nucleotide 3005-3024 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:68.In some such embodiment, the antisense compounds of the Nucleotide 3005-3024 of target SEQ ID NO:3 is selected from ISIS NO:395193 or 399915.

In certain embodiments, target region is the Nucleotide 3005-3174 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 3005-3174.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:68,431,432,433,434,69,435,436,437,438 or 70 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3005-3174 of target SEQID NO:3 is selected from ISIS NO:395193,399915,405893,405894,405895,405896,395194,399916,405897,405898,405899,405900,395195 or 399917.

In certain embodiments, target region is the Nucleotide 3083-3110 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 3083-3110.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:69,69,431,432,433,434,435,436,437 or 438 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3083-3110 of target SEQ IDNO:3 is selected from ISIS NO:395194,399916,405893,405894,405895,405896,405897,405898,405899 or 405900.

In certain embodiments, target region is the Nucleotide 3155-3184 of SEQ ID NO:3.In certain embodiments, antisense compounds targeted nucleotide 3155-3184.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:70,71,439,440,441,442,443,444,445 or 446 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3155-3184 of target SEQ IDNO:3 is selected from ISIS NO:395195,399821,399917,399977,405901,405902,405903,405904,405905,405906,405907 or 405908.

In certain embodiments, target region is the Nucleotide 3238-3268 of SEQ ID NO:3.In certain embodiments, the Nucleotide 3238-3268 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:72,73 or 135 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3238-3268 of target SEQ ID NO:3 is selected from ISIS NO:395196,399822,399823,399918,399978 or 399979.

In certain embodiments, target region is the Nucleotide 3482-3711 of SEQ ID NO:3.In certain embodiments, the Nucleotide 3482-3711 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises and is selected from SEQ ID NO:74,75 or 112 nucleotide sequence.In some such embodiment, the antisense compounds of the Nucleotide 3482-3711 of target SEQ ID NO:3 is selected from ISIS NO:395197,395198,399824,399919,399920 or 399980.

In certain embodiments, target region is the Nucleotide 3727-3751 of SEQ ID NO:3.In certain embodiments, the Nucleotide 3727-3751 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:76 or 77.In some such embodiment, the antisense compounds of the Nucleotide 3727-3751 of target SEQ ID NO:3 is selected from ISIS NO:395199,399921,399825 or 399981.

In certain embodiments, target region is the Nucleotide 3798-3824 of SEQ ID NO:3.In certain embodiments, the Nucleotide 3798-3824 of antisense compounds target SEQ ID NO:3.In certain embodiments, the antisense compounds of target PCSK9 nucleic acid comprises the nucleotide sequence that is selected from SEQ ID NO:78 or 99.In some such embodiment, the antisense compounds of the Nucleotide 3798-3824 of target SEQ ID NO:3 is selected from ISIS NO:395200,399922,399826 or 399982.

In certain embodiments, short gap polymers antisense compounds target PCSK9 nucleic acid.In some such embodiment, breach polymers antisense compounds target SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3.In some such embodiment, illustrative nucleotide sequence has 2-10-2 breach polymers motif in the table 14.1.Table 14.1 illustration the breach polymers antisense compounds of target SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3, it has the 2-10-2 motif, wherein the breach section comprises 2 '-deoxynucleotide, and each pterion Duan Jun comprises and has the sugar-modified Nucleotide of 2 '-O-methoxyethyl.Be connected to thiophosphatephosphorothioate between nucleosides, and cytidine is the 5-methylcytidine.

Table 14.1: the breach polymers antisense compounds of target SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3 with 2-10-2 motif

Target SEQ ID NO	ISIS number	Motif	The oligomer sequence	5 ' target site on the SEQ ID NO:1	3 ' target site on the SEQ ID NO:1	SEQ ID NO
							1	406539	2-10-2	GCCTATGAGGGTGC	1079	1092	458
1	406540	2-10-2	TCCAGGCCTATGAG	1084	1097	459
							1	406551	2-10-2	CAGCTCAGCAGCTC	1735	1748	460
1	406595	2-10-2	TTAATCAGGGAGCC	2877	2890	461
							2	406551	2-10-2	CAGCTCAGCAGCTC	21181	21194	460
2	406595	2-10-2	TTAATCAGGGAGCC	26684	26697	461
							3	406539	2-10-2	GCCTATGAGGGTGC	1609	1622	458
3	406540	2-10-2	TCCAGGCCTATGAG	1614	1627	459
							3	406551	2-10-2	CAGCTCAGCAGCTC	2168	2181	460
3	406595	2-10-2	TTAATCAGGGAGCC	3132	3145	461

In certain embodiments, lack antisense compounds and have the effectiveness of comparing increase with the compound of 20 Nucleotide.In certain embodiments, the such short antisense compounds and the targeting compounds same area of 20 Nucleotide.In certain embodiments, lack antisense compounds and have the effectiveness of comparing increase with the compound of 20 Nucleotide of the sequence that contains described short antisense compounds.

In certain embodiments, desired effects is the reduction of mRNA target nucleic acid level.In other embodiments, desired effects is to be changed by the reduction of target nucleic acid encoded protein matter level or the phenotype relevant with this target nucleic acid.

In one embodiment, target region is the zone that structurally limits in the nucleic acid.For example, the nucleic acid district of 3 ' UTR, 5 ' UTR, exon, intron, coding region, translation initiation district, translation termination district or other qualification can be contained in the target area.In other embodiments, the sequence of the target region 5 ' target site that can contain a target area section in this target region 3 ' target site of another target area section to this target region.

The target process comprises at least one target area section of determining antisense compounds and its hybridization (producing desired effects thus).Target region can contain one or more target areas section.A plurality of target areas section in the target region can overlap.Perhaps, they can not overlap.In one embodiment, each the target area section in the target region is separated mutually by no more than about 10 Nucleotide on the target nucleic acid.In another embodiment, each the target area section in the target region is separated mutually by no more than about 5 Nucleotide on the target nucleic acid.In other embodiment, the target area section is a successive.

Suitable target area section can be present in 5 ' UTR, coding region, 3 ' UTR, intron or the exon.The target area section that contains initiator codon or terminator codon also is suitable target area section.

Compare the sequence of target nucleic acid and other sequence of whole genome definite can the comprising of suitable target area section.For example, can use the BLAST algorithm in the middle of different nucleic acid, to identify zone with similarity.This comparison can prevent to select may be with the antisense compounds sequence of the sequence outside non-specific mode and the selected target nucleic acid (being the non-target or the sequence of missing the target (non-target or off-target sequences)) hybridization.

Can there be variation (for example, reduce as the per-cent by the target nucleic acid level define) in the activity of antisense compounds in active target region.In one embodiment, the reduction of PCSK9mRNA level shows the inhibition that PCSK9 is expressed.The reduction of PCSK9 protein level also shows the inhibition that said target mrna is expressed.In addition, phenotype changes the inhibition that shows the PCSK9 expression.For example, the reduction of LDL-C level shows the inhibition that PCSK9 is expressed.

Hybridization

For example, hybridization can occur between antisense compounds disclosed herein and the PCSK9 nucleic acid.The hydrogen bonding (for example, Watson-Crick, Hoogsteen or oppositely Hoogsteen hydrogen bonding) between the base is examined in the complementation that modal hybridization mechanism relates to nucleic acid molecule.

Hybridization can take place under different conditions.Stringent condition depends on sequence, and by the character of nucleic acid molecule to be hybridized with form decision.

Whether measure sequence can be well known in the art with the method for target nucleic acid specific hybrid.In one embodiment, antisense compounds provided herein can be hybridized with PCSK9 nucleic acid specificity ground.

Complementary

When the nuclear base of the antisense compounds of enough numbers can be with in the target nucleic acid during corresponding nuclear base hydrogen bonding, described antisense compounds and described target nucleic acid are complimentary to one another, to produce the effect (for example, to the Antisense Suppression of target nucleic acid) of expectation thus such as PCSK9 nucleic acid.

Incomplementarity nuclear base between antisense compounds and the PCSK9 nucleic acid can be tolerated, as long as this antisense compounds still can be hybridized specifically with target nucleic acid.In addition, antisense compounds can hybridize on one or more sections of PCSK9 nucleic acid, makes to interleave or adjacent sections does not relate in hybridisation events (for example, ring structure, mispairing or hairpin structure).

In some embodiments, antisense compounds provided herein and PCSK9 nucleic acid are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% complementary.The per-cent complementarity of antisense compounds and target nucleic acid can use ordinary method to measure.

In other embodiments, antisense compounds provided herein and target nucleic acid fully complementary (that is 100% complementation).For example, antisense compounds can be and the complete complementary of PCSK9 nucleic acid.As used herein, " fully complementary " is meant that each nuclear base of antisense compounds can both carry out accurate base pairing with the corresponding nuclear base of target nucleic acid.

The position of incomplementarity nuclear base can be at the 5 ' end or the 3 ' end of antisense compounds.Perhaps, one or more incomplementarity nuclear bases can be at the interior location of antisense compounds.When having two or more incomplementarity nuclear bases, they can be successive (promptly linking to each other) or discontinuous.In one embodiment, incomplementarity nuclear base is positioned at the pterion section of breach polymers antisense oligonucleotide.

In one embodiment, the antisense compounds of 20 nuclear of length as many as base comprises no more than 4, no more than 3, no more than 2 or no more than 1 incomplementarity nuclear base with respect to target nucleic acid such as PCSK9 nucleic acid.

In another embodiment, the antisense compounds of 30 nuclear of length as many as base comprises no more than 6, no more than 5, no more than 4, no more than 3, no more than 2 or no more than 1 incomplementarity nuclear base with respect to target nucleic acid such as PCSK9 nucleic acid.

Antisense compounds provided herein also comprises a part of complementary of those and target nucleic acid.As used herein, " part " is meant successive (promptly linking to each other) the nuclear base that ascertains the number in zone of target nucleic acid or the section.One " part " also can refer to the antisense compounds purpose continuous kernel base of fixing a number really.In one embodiment, the part of one at least 8 of antisense compounds and target area section nuclear bases is complementary.In another embodiment, the part of one at least 12 of antisense compounds and target area section nuclear bases is complementary.In another embodiment, the part of one at least 15 of antisense compounds and target area section nuclear bases is complementary.

Identity

Antisense compounds provided herein also can have definite and specific nucleotide sequence, SEQ IDNO or by the per-cent identity of the compound of specific Isis numbering representative.As used herein, if antisense compounds has the nuclear base pairing ability identical with sequence disclosed herein, this antisense compounds and this sequence disclosed herein are same so.For example, replace the thymus pyrimidine in the disclosed dna sequence dna and the RNA that contains uridylic can be considered to this dna sequence dna be same because uridylic and thymus pyrimidine all match with VITAMIN B4.Also contain the shortening and the prolongation form of antisense compounds described herein and have compound with respect to the non-same base of antisense compounds provided herein.Non-same base can be adjacent one another are or be dispersed in the whole antisense compounds.The per-cent identity of antisense compounds is calculated according to the base number that has same base pairing with respect to the sequence that compares with it.

In one embodiment, antisense compounds and one or more antisense compounds at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% disclosed herein or 100% are same.

Modify

Nucleosides is base-sugar combination.Nuclear base (the being also referred to as base) part of nucleosides is the heterocyclic base module normally.Nucleotide is the nucleosides that further comprises with the covalently bound phosphate group of the sugar moieties of nucleosides.Comprise the nucleosides of furan pentose (pentofuranosyl sugar) for those, phosphate group can with 2 of sugar ', 3 ' or 5 ' hydroxyl module be connected.Oligonucleotide is by the covalently bound each other formation of adjacent nucleosides, thus formation linear polymerization oligonucleotide.In oligonucleotide structure, connect between the nucleosides that claims phosphate group to form oligonucleotide usually.

To the modification of antisense compounds comprise substitute or change between nucleosides connect, sugared module or nuclear base.The modified antisense compound is normally preferred with respect to natural form, and reason is the character of expectation, such as, for example, enhanced cell picked-up, enhanced are to the stability of the avidity of nucleic acid target, increase when nuclease exists or the inhibition activity that increases.

The nucleosides of chemically modified also can be used to increase the binding affinity of the antisense oligonucleotide of shortening or brachymemma to its target nucleic acid.Therefore, use short antisense compounds can obtain suitable result usually with this class chemically modified nucleoside.

Connect between the nucleosides of modifying

Be connected between naturally occurring nucleosides among RNA and the DNA be 3 ' to 5 ' phosphodiester connect.Have one or more modifications, be that non-natural exists, the antisense compounds that connects between nucleosides is preferable over usually has the antisense compounds that connects between naturally occurring nucleosides, reason is the character of expectation, such as, for example, enhanced cell picked-up, enhanced are to the avidity of target nucleic acid and the stability that increases when nuclease exists.

Having the oligonucleotide that connects between the nucleosides of modification comprises between the nucleosides that keeps phosphorus atom between the nucleosides that connects and do not contain phosphorus atom and connecting.Connect between representational phosphorous nucleosides and comprise, but be not limited to phosphodiester (phosphodiester), phosphotriester (phosphotriester), methylphosphonate (methylphosphonate), phosphoramidate (phosphoramidate) and thiophosphatephosphorothioate (phosphorothioate).Phosphorous and the not phosphorous preparation method who is connected is known.

In one embodiment, the antisense compounds of target PCSK9 comprises between the nucleosides of one or more modifications and connects.In some embodiments, connecting between the nucleosides of modification is that thiophosphatephosphorothioate connects.In other embodiments, connect between each nucleosides of antisense compounds to be between the thiophosphatephosphorothioate nucleosides and connect.

The sugared module of modifying

The antisense compounds of target PCSK9 nucleic acid can contain one or more Nucleotide with sugared module of modification.The sugar-modified antisense compounds of can giving is with other useful biological characteristics of nuclease stability, binding affinity or some.The furanose ring of nucleosides can be modified in several ways, includes, but are not limited to: add substituting group, particularly in 2 ' position; Two non-(non-geminal) annular atomses in pairs of bridge joint are to form dicyclo nucleic acid (BNA); With with atom or group such as-S-,-N (R)-or-C (R ₁) (R ₂) replace 4 '-epoxy of position.The sugar of modifying includes, but are not limited to: the sugar of replacement, especially have 2 '-F, 2 '-OCH ₂, (2 '-OMe) or 2 '-O (CH ₂) ₂-OCH ₃(2 '-O-methoxyethyl or 2 '-MOE) substituent 2 '-sugar that replaces; With the sugar (BNA) of the modification of dicyclo, it has 4 '-(CH ₂) _n-O-2 ' bridge joint, wherein n=1 or n=2 comprise inferior methoxyl group (the 4 '-CH of α-L- ₂-O-2 ') inferior methoxyl group (the 4 '-CH of BNA, β-D- ₂-O-2 ') BNA and inferior ethoxyl (4 '-(CH ₂) ₂-O-2 ') BNA.The sugar of the modification of dicyclo also comprises (6 ' S)-6 ' methyl BNA, aminooxy (4 '-CH ₂-O-N (R)-2 ') BNA, oxygen amino (4 '-CH ₂-N (R)-O-2 ') BNA, wherein R is H, blocking group or C1-C12 alkyl independently.The substituting group of 2 ' position also can be selected from allyl group, amino, azido-, sulfo-, O-allyl group, O-C1-C10 alkyl, OCF ₃, O (CH ₂) ₂SCH ₃, O (CH ₂) ₂-O-N (R _m) (R _n) and O-CH ₂-C (=O)-N (R _m) (R _n), each R wherein _mAnd R _nBe the C1-C10 alkyl of H or replacement or non-replacement independently.In certain embodiments, the Nucleotide that such BNA modifies is the Nucleotide of high-affinity, they is mixed antisense compounds make effectiveness increase and feasible treatment index improve.The method that is used to prepare the sugar of modification is well known to a person skilled in the art.

In the Nucleotide of sugared module, for the hybridization with suitable nucleic acid target keeps nuclear base module (natural, that modify or its combination) with modification.

In one embodiment, the antisense compounds of target PCSK9 nucleic acid comprises one or more Nucleotide with sugared module of modification.In a suitable embodiment, the sugared module of modification is 2 '-MOE.In other embodiments, the Nucleotide that 2 '-MOE is modified is arranged in the breach polymers motif.

The nuclear base of modifying

Nuclear base (or base) is modified or is replaced structurally and can differentiate with naturally occurring or synthetic unmodified nuclear base, and can exchange on function.The natural nuclear base with modifying all can participate in hydrogen bonding.Such nuclear base modification can give nuclease stability, binding affinity or some other useful biological characteristics for antisense compounds.The nuclear base of modifying comprise synthetic and natural nuclear base such as, for example, 5-methylcytosine (5-me-C).Some nuclear base replaces, and comprises that 5-methylcytosine replaces, and is useful especially for increasing antisense compounds to the binding affinity of target nucleic acid.For example, proved that the 5-methylcytosine replacement makes nucleic acid duplex stability increase 0.6-1.2 ℃ of (Sanghvi, Y. S., Crooke, S.T. and Lebleu, B. edit, Antisense Research andApplications, CRC Press, Boca Raton, 1993, the 276-278 pages or leaves).

Other unmodified nuclear base comprises the 2-propyl group of the 6-methyl of 5-hydroxymethyl cytosine, xanthine, xanthoglobulin, 2-aminoadenine, VITAMIN B4 and guanine and other alkyl derivative, VITAMIN B4 and guanine and other alkyl derivative, 2-thiouracil, 2-sulphur thymus pyrimidine and 2-sulphur cytosine(Cyt), 5-halo uridylic and cytosine(Cyt), 5-proyl (C ≡ C-CH ₃) other alkynyl derivatives of uridylic and cytosine(Cyt) and pyrimidine bases, 6-azo uridylic, cytosine(Cyt) and thymus pyrimidine, 5-uridylic (pseudouracil), the 4-thiouracil, the 8-halo, 8-amino, the 8-sulfydryl, 8-sulfo-alkyl, VITAMIN B4 and guanine that 8-hydroxyl and other 8-replace, the 5-halo is the 5-bromo particularly, uridylic and cytosine(Cyt) that 5-trifluoromethyl and other 5-replace, 7-methyl guanine and 7-methyladenine, the 2-F-VITAMIN B4,2-amino-VITAMIN B4,8-azaguanine and 8-nitrogen VITAMIN B4,7-deazaguanine and 7-denitrogenation VITAMIN B4 and 3-deazaguanine and 3-denitrogenation VITAMIN B4.

The heterocyclic base module can comprise that also those wherein replace purine or pyrimidine bases with other heterocycle, for example 7-denitrogenation-VITAMIN B4,7-denitrogenation guanosine, 2-aminopyridine and 2-pyridone.Comprise pyrimidine, 6-aza-pyrimidine and N-2, the N-6 of 5-replacement and the purine that O-6 replaces for the useful especially nuclear base of binding affinity that increases antisense compounds, comprise 2-aminopropyl VITAMIN B4,5-proyl uridylic and 5-proyl cytosine(Cyt).

In one embodiment, the antisense compounds of target PCSK9 nucleic acid comprises the nuclear base of one or more modifications.In an other embodiment, the antisense oligonucleotide that the breach of target PCSK9 nucleic acid is widened comprises the nuclear base of one or more modifications.In some embodiments, the nuclear base of modification is a 5-methylcytosine.In further embodiment, each cytosine(Cyt) all is a 5-methylcytosine.

Composition and be used for the compounding pharmaceutical method for compositions

Antisense oligonucleotide can be mixed with pharmaceutical compositions or preparaton with pharmacy acceptable activity and/or inert substance.Composition and be used for the compounding pharmaceutical method for compositions and depend on multiple standards, the dosage that include, but not limited to route of administration, disease degree, maybe will use.

By the antisense compounds of target PCSK9 nucleic acid and suitable pharmacy can be accepted the diluent or carrier combination, can in pharmaceutical composition, use described antisense compounds.Pharmacy can be accepted thinner and comprise phosphate buffered saline (PBS) (PBS).PBS is adapted at the thinner that uses in the composition of parenteral delivery.Thereby in one embodiment, what use in method described herein is to comprise the antisense compounds of target PCSK9 nucleic acid and the pharmaceutical composition that pharmacy can be accepted thinner.In one embodiment, the pharmacy acceptable diluent is PBS.In other embodiments, antisense compounds is an antisense oligonucleotide.

The pharmaceutical composition that comprises antisense compounds comprises the salt of any pharmacologically acceptable salts, ester or these esters, or any other oligonucleotide, and it can (directly or indirectly) provide its biologic activity metabolite or resistates when animal comprises that the people uses.Thereby for example, this paper also relates to pharmaceutically acceptable salt, the prodrug (prodrug) of antisense compounds, pharmaceutically acceptable salt and other bioequivalence thing of these prodrugs.Suitable pharmaceutically acceptable salt includes, but not limited to sodium salt and sylvite.

Prodrug can be included in the one or both ends of antisense compounds and mix extra nucleosides, and described nucleosides downcuts by the endogenous nucleic acid enzyme in vivo, to form active antisense compounds.

In certain embodiments, pharmaceutical composition of the present invention comprises one or more oligonucleotide and one or more vehicle.In some such embodiment, vehicle is selected from water, salts solution, alcohol, polyoxyethylene glycol, gelatin, lactose, amylose starch (amylase), Magnesium Stearate, talcum, silicic acid, viscous paraffin (viscous paraffin), Walocel MT 20.000PV and polyvinylpyrrolidone.

In certain embodiments, pharmaceutical composition of the present invention is to use the known technology preparation, described known technology comprises, but be not limited to, mix, dissolving, granulate, sugaring garment piece (dragee-making), grind (levigating), emulsification, packing (encapsulating), parcel (entrapping) or compressing tablet process into powder.

In certain embodiments, pharmaceutical composition of the present invention is liquid (for example suspension, elixir and/or a solution).In some such embodiment, liquid pharmaceutical composition is to use composition known in the art to prepare, and described composition includes, but are not limited to water, glycol, oil, alcohol, perfume compound, sanitas and tinting material.

In certain embodiments, pharmaceutical composition of the present invention is solid (for example pulvis, tablet and/or a capsule).In some such embodiment, the solid pharmaceutical composition that comprises one or more oligonucleotide is to use composition known in the art to prepare, described composition includes, but are not limited to starch, sugar, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent.

In certain embodiments, pharmaceutical composition of the present invention is formulated as prolonged action preparation (depotpreparation).Some such prolonged action preparation is usually than the long action time of nonpersistent effect reagent.In certain embodiments, such preparation is to use by implanting (for example subcutaneous or intramuscular) or intramuscular injection.In certain embodiments, prolonged action preparation is to use suitable polymeric material or hydrophobic material (for example emulsion in acceptable oil) or ion exchange resin to prepare, or is prepared as the derivative of microsolubility, for example salt of microsolubility.

In certain embodiments, pharmaceutical composition of the present invention comprises delivery system.The example of delivery system includes, but are not limited to liposome and emulsion.Some delivery system comprises that for preparation some drugs composition those pharmaceutical compositions that comprise hydrophobic compound are useful.In certain embodiments, use some organic solvent, for example methyl-sulphoxide.

In certain embodiments, pharmaceutical composition of the present invention comprises one or more tissue specificities and sends molecule, and these molecules are designed to one or more drug delivery of the present invention to specific tissue or cell type.For example, in certain embodiments, pharmaceutical composition comprises the liposome with the tissue specificity antibody sandwich.

In certain embodiments, pharmaceutical composition of the present invention comprises the cosolvent system.Some such cosolvent system comprises, for example, and phenylcarbinol, non-polar surfactant, organic polymer and water that can be miscible with water.In certain embodiments, such cosolvent system is used for hydrophobic compound.A limiting examples of such cosolvent system is a VPD cosolvent system, and it is the phenylcarbinol that comprises 3%w/v, the non-polar surfactant Polysorbate 80 of 8%w/v ^TMEthanol solution with the Liquid Macrogol of 65%w/v.Can carry out bigger variation to the ratio of such cosolvent system and significantly do not change their solvability and toxic characteristic.In addition, can change the identity of cosolvent component: for example, can use other tensio-active agent to replace Polysorbate 80 ^TMCan change the fraction size (fraction size) of polyoxyethylene glycol; Can with other biocompatible polymer for example polyvinylpyrrolidone replace polyoxyethylene glycol; Can also replace dextrose with other sugar or polysaccharide.

In certain embodiments, pharmaceutical composition of the present invention comprises sustained release system.The semipermeability matrix that a limiting examples of such sustained release system is solid-state hydrophobic polymer.In certain embodiments, depend on their chemical property, sustained release system can in hour, in day, release medicine in week or in the time period of the moon.

In certain embodiments, preparation of pharmaceutical compositions of the present invention is used for Orally administered.In some such embodiment, pharmaceutical composition is prepared by one or more oligonucleotide are mixed with one or more pharmaceutically acceptable carriers.Some such carrier makes pharmaceutical composition can be formulated as tablet, pill, coated tablet, capsule, liquid, gelifying agent, syrup, paste, suspension or the like, for experimenter's orally ingestible.In certain embodiments, the pharmaceutical composition that Gong orally uses is by obtaining oligonucleotide and the mixing of one or more solid excipients.Suitable vehicle includes, but are not limited to: weighting agent such as sugar, comprises lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; The preparation of cellulose thing such as, for example W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragakanta, methylcellulose gum, hydroxypropylmethyl-Mierocrystalline cellulose, Xylo-Mucine and/or polyvinylpyrrolidone (PVP).In certain embodiments, randomly such mixture is ground and chooses wantonly interpolation auxiliary material (auxiliaries).In certain embodiments, with the pharmaceutical composition moulding to obtain tablet or coated tablet core.In certain embodiments, add disintegrating agent (for example, crosslinked polyvinylpyrrolidone, agar or Lalgine or its salt are such as sodium alginate).

In certain embodiments, the coated tablet core is provided with dressing.In some such embodiment, can use concentrated sugar solution, it can randomly contain gum arabic, talcum, polyvinylpyrrolidone, Carbopol gel, polyoxyethylene glycol and/or titanium dioxide, lacquer (lacquer) solution and appropriate organic solvent or solvent mixture.Can in tablet or coated tablet dressing, add dyestuff or pigment.

In certain embodiments, be sucking fit formula (push-fit) capsule made from gelatin for Orally administered pharmaceutical composition.Some such sucking fit formula capsule comprises one or more medicines of the present invention and one or more weighting agents of blended (such as lactose), tackiness agent (such as starch) and/or lubricant (such as talcum or Magnesium Stearate) with it, and optional stablizer.In certain embodiments, for Orally administered pharmaceutical composition be the soft capsule of the sealing made from gelatin and softening agent (such as glycerine or sorbyl alcohol).In some soft capsule, one or more medicaments of the present invention dissolve or are suspended in the suitable liquid these liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol.In addition, can add stablizer.

In certain embodiments, preparation of pharmaceutical compositions is used for being used to contain clothes.Some such pharmaceutical composition is tablet or the lozenge of preparing in a usual manner.

In certain embodiments, preparation of pharmaceutical compositions is used for being used for injection (for example intravenously, subcutaneous, intramuscular, or the like).In some such embodiment, pharmaceutical composition comprises carrier, and is formulated in the aqueous solution, such as water or physiological compatibility damping fluid such as Han Kesishi (Hanks) solution, woods Ge Shi (Ringer) solution or normal saline buffer solution.In certain embodiments, comprise other composition (for example, helping to dissolve or serve as the composition of sanitas).In certain embodiments, use suitable liquid carrier, suspension agent to wait and prepare injectable suspensions.Some medicinal composition for injections provides with unit dosage form (unit dosage form), for example, and in ampoule or multi-dose container.Some medicinal composition for injections is suspension, solution or the emulsion in oiliness or the aqueous media, can comprise preparation and use reagent (formulatory agents) such as suspension agent, stablizer and/or dispersion agent.Some solvent that is adapted at using in the medicinal composition for injections includes, but are not limited to: lipophilic solvent and fatty oil, such as sesame oil; Acrawax is such as ethyl oleate or tri-glyceride; And liposome.Aqueous injection suspension can comprise the material that can increase suspension viscosity, such as Xylo-Mucine, sorbyl alcohol or dextran.Randomly, such suspension also can comprise the agent that suitable stabilizers maybe can increase medicament solubleness, thereby can prepare highly spissated solution.

In certain embodiments, with preparation of pharmaceutical compositions for being used for mucosal administration.In some such embodiment, in preparaton, use the penetration agent be suitable for the barrier that will penetrate.Such penetration agent is known in the art.

In certain embodiments, preparation of pharmaceutical compositions is used for being used for sucking.Some such inhaled medication compositions is prepared as the form that is contained in the sprays in pressurized package or the spraying gun.Some such pharmaceutical composition comprises propelling agent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Use in the embodiment of pressurized aerosol at some, can utilize the valve of metered delivery to decide dose unit.In certain embodiments, can prepare capsule or the cartridge case (cartridges) that is used for sucker or insufflator.Some such preparaton comprises the powdered mixture that medicament of the present invention is become with suitable powder matrix (such as lactose or starch).

In certain embodiments, with preparation of pharmaceutical compositions for being used for rectal administration, such as suppository or enema,retention.Some such pharmaceutical composition comprises known component, such as theobroma oil and/or other glyceryl ester.

In certain embodiments, with preparation of pharmaceutical compositions for being used for surface applied.Some such pharmaceutical composition comprises gentle humidification substrate, such as ointment or emulsifiable paste.Exemplary suitable ointment substrate includes but not limited to that vaseline, vaseline add volatile silicone, lanolin and water-in-oil emulsion, such as Eucerin ^TM, can available from Beiersdorf (Cincinnati, Ohio).Exemplary suitable emulsifiable paste substrate includes but not limited to Nivea ^TMEmulsifiable paste can be available from Beiersdorf (Cincinnati.Ohio), cold cream (USP), Purpose Cream ^TM, can be available from Johnson﹠amp; Johnson (New Brunswick, N.J.), hydrophilic soft paste (USP) and Lubriderm ^TM, can available from Pfizer (Morris Plains, N.J.).

In certain embodiments, pharmaceutical composition of the present invention comprises the oligonucleotide for the treatment of significant quantity.In certain embodiments, the treatment significant quantity is enough to prevent, alleviate or improves the symptom of disease or the experimenter's that prolongation is treated survival.Determining fully within those skilled in the art's limit of power of treatment significant quantity.

In certain embodiments, one or more oligonucleotide of the present invention are formulated as prodrug.In certain embodiments, when using in vivo, prodrug by chemical transformation be described oligonucleotide biologically, pharmaceutically or the treatment on more activated form.In certain embodiments, why useful prodrug is, is because they are used than corresponding activity form is easier.For example, in some cases, prodrug can be easier to biological utilisation (for example, by Orally administered) than corresponding activity form.In some cases, prodrug is compared with corresponding activity form and can be had better solvability.In certain embodiments, prodrug water-soluble low than corresponding activity form.In some cases, such prodrug has the good cytolemma transitivity of wearing, and water-soluble herein is deleterious to mobility.In certain embodiments, prodrug is an ester.In some such embodiment, described ester is hydrolyzed into carboxylic acid by metabolism when using.In some cases, the compound that contains carboxylic acid is corresponding activity form.In certain embodiments, prodrug comprises the small peptide (polyamino acid) that is incorporated into acid groups.In some such embodiment, described peptide is cut when using, and forms corresponding activity form.

In certain embodiments, the generation of prodrug is by modifying the compound of pharmaceutical active, making that this active compound will be regenerated when using in vivo.Can design prodrug, with the metabolic stability that changes medicine or transport feature, shelter side effect or toxicity, improve the taste of medicine or change the further feature or the character of medicine.By knowledge to drug disposition metabolism and pharmacodynamics process, in case known certain pharmaceutical active compounds, those skilled in the art just can design the prodrug of this compound (referring to for example Nogrady (1985) Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, the 388-392 page or leaf).

In certain embodiments, the pharmaceutical composition that comprises one or more medicaments of the present invention is in mammalian subject, and particularly treatment illness or illness are useful among the people experimenter.That suitable route of administration includes, but are not limited to is oral, rectum, through mucous membrane, intestines (intestinal), enteron aisle (enteral), surface, suppository, by suck, in the sheath, in indoor, the intraperitoneal, nose, intraocular and non-digestive tract (for example in intravenously, intramuscular, the marrow and subcutaneous).In certain embodiments, the interior drug administration (pharmaceuticalintrathecals are administered) of sheath is to realize the exposure of part rather than whole body.For example, pharmaceutical composition can be injected directly in the zone of expecting to work (for example kidney or heart area).

In certain embodiments, pharmaceutical composition of the present invention is used with the form of dose unit (for example, tablet, capsule, bolus (bolus)).In certain embodiments, such pharmaceutical composition comprises the oligonucleotide that is selected from following dosage: 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg and 800mg.In some such embodiment, pharmaceutical composition of the present invention comprises the oligonucleotide that is selected from following dosage: 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 500mg, 600mg, 700mg and 800mg.In certain embodiments, pharmaceutical composition comprises the oligonucleotide that is selected from following dosage: 50mg, 100mg, 150mg, 200mg, 250mg, 300mg and 400mg.In certain embodiments, according to scope for from every day more than once, once a day, once in a week, twice weekly, on every Wendesdays time, on every Thursdays time, on every Fridays time, on every Saturdays time, once used described dosage in every month, in order on time span as required, to keep desired effects to trimestral interval.

In yet another aspect, medicament is aseptic freeze-dried oligonucleotide, and it is rebuild with suitable diluent (for example sterile water for injection).After being diluted to the product of rebuilding in the salt solution, use as subcutaneous injection or intravenous infusion.The oligonucleotide that constitutes described freeze-dried drug product prepares in water for injection, during preparation is adjusted to pH 7.0-9.0, freeze-drying then with acid or alkali.Freeze dried oligonucleotide can be the oligonucleotide of 25-800mg.Should understand this and contain 25,50,75,100,125,150,175,200,225,250,275,300,325,350,375,400,425,450,475,500,525,550,575,600,625,650,675,700,725,750,775 and the freeze-drying oligonucleotide of 800mg.Freeze dried medicament production can be packaged in the tubular bottle of the I type transparent glass of 2mL (handling through ammonium sulfate), chlorinated butyl rubber bung beyond the Great Wall, and use aluminum FLIP-

Closedtop (overseal) is sealed.In one embodiment, lyophilized medication comprises ISIS 301012.

Composition of the present invention can comprise routine extraly and be present in other auxiliary component in the pharmaceutical composition, and these components adopt dosage level that their establish in this area.So, for example, described composition can comprise other compatible pharmaceutically active substances, such as, for example pruritus, astringent matter, local anesthetic or anti-inflammatory agent, perhaps can comprise other for the useful material of various dosage forms with the physical method preparation present composition, for example dyestuff, perfume compound, sanitas, antioxidant, opalizer, thickening material and stablizer.Yet these materials bring improperly should not for when adding the biologic activity of each component in the present composition and disturb.Can be with described preparaton sterilization, and if desired, can with they with can harmful interactional assistant agent not to take place with the oligonucleotide of described preparaton not mix, described assistant agent is lubricant, sanitas, stablizer, wetting agent, emulsifying agent, the salt that is used to influence osmotic pressure, buffer reagent, tinting material, seasonings and/or spices or the like for example.

The antisense compounds of puting together

Antisense compounds can be covalently bound with one or more modules or conjugate, and described module or conjugate strengthen activity, cell distribution or the cellular uptake of gained antisense oligonucleotide.Typically put together group and comprise cholesterol module and lipid module.Other is puted together group and comprises carbohydrate, phosphatide, vitamin H, azophenlyene, folate, phenanthridines (phenanthridine), anthraquinone (anthraquinone), acridine (acridine), fluorescein, rhodamine (rhodamine), tonka bean camphor (coumarin) and dyestuff.

Also can modify antisense compounds so that it has one or more stable groups, described stable group is attached to the one or both ends of antisense compounds usually to strengthen such as character such as for example nuclease stability.Stablize and comprise cap structure in the group.The antisense compounds that these end modified protections have terminal nucleic acid avoids by the exonuclease enzyme liberating, and can help to send and/or locate intracellular.Cap may reside in 5 '-terminal (5 '-cap), or 3 '-terminal (3 '-cap), perhaps can be present in two ends simultaneously.Cap structure is well known in the art, and comprises, for example, oppositely deoxidation does not have base cap (inverted deoxy abasiccap).Can be used for adding in the one or both ends of antisense compounds cap with give nuclease stability other 3 ' and 5 '-stablize WO 03/004602 disclosure that group comprises that those were announced on January 16th, 2003.

Cell cultures and antisense compounds are handled

Antisense compounds can carry out vitro test to level, the activity of PCSK9 nucleic acid or the effect of expressing in the various kinds of cell type.The cell type that is used for this alanysis can go into business industry dealer (American type culture collection (American Type Culture Collection) for example, Manassus, VA; Zen-Bio, Inc., Research Triangle Park, NC; Clonetics Corporation, Walkersville MD) obtains, and (Invitrogen LifeTechnologies for example, Carlsbad CA) comes culturing cell to use commercially available reagent according to dealer's guidance.The exemplary cells type includes, but not limited to HepG2 cell, HepB3 cell and primary hepatocyte.

The vitro test of antisense oligonucleotide

Described herein is the method for handling cell with antisense oligonucleotide, can suitably revise described method for the processing of carrying out with other antisense compounds.

Generally, when cell reaches the degree of converging of about 60-80% in cultivation, handle cell with antisense oligonucleotide.

A kind of being usually used in comprises the cation lipid transfection reagent with the reagent that antisense oligonucleotide is introduced in the cultured cells

(Invitrogen, Carlsbad, CA).With antisense oligonucleotide with

1 (Invitrogen, Carlsbad, CA) middle mixing, antisense oligonucleotide final concentration and the common scope expected with realization are every 100nM antisense oligonucleotide 2-12ug/mL's

Concentration.

The another kind of reagent that is used for antisense oligonucleotide is introduced cultured cells comprises

(Invitrogen, Carlsbad, CA).With antisense oligonucleotide with

1 subtracts blood serum medium (reduced serum medium), and (CA) the middle mixing is every 100nM antisense oligonucleotide 2-12ug/mL's with antisense oligonucleotide concentration and the common scope that realizes expectation for Invitrogen, Carlsbad

Concentration.

Cell is handled with antisense oligonucleotide by ordinary method.Usually 16-24 hour harvested cell after antisense oligonucleotide is handled, RNA or protein level by methods known in the art and method described herein measurement target nucleic acid during results.Usually, when handling, the mean value of data as re-treatment is presented with a plurality of repeating.

The concentration of the antisense oligonucleotide that uses is different because of the difference of clone.The method of measuring the antisense oligonucleotide optimum concn for specific cells system is known in the art.The concentration range of normally used antisense oligonucleotide is 1nM-300nM.

RNA separates

Can carry out the RNA analysis to total cell RNA or poly-(A)+mRNA.The isolating method of RNA is well known in the art.Use method well known in the art to prepare RNA, for example, use

(CA) scheme according to manufacturer recommendation prepares RNA to reagent for Invitrogen, Carlsbad.

Analysis to the inhibition of target thing level or expression

Can measure according to multiple mode known in the art the level of PCSK9 nucleic acid or the inhibition of expression.For example, can come the quantifying target nucleic acid level by for example Northern engram analysis, competitive polymerase chain reaction (PCR) or quantitative PCR in real time.Can carry out the RNA analysis to total cell RNA or poly-(A)+mRNA.The RNA separation method is well known in the art.The Northern engram analysis also is the ordinary method of this area.Quantitatively PCR in real time can be finished easily, wherein uses commercially available ABI

7600,7700 or 7900 sequence detection systems, it can be from PE-Applied Biosystems, Foster City, CA obtains, and uses according to the specification sheets of manufacturers.

Quantitative PCR in real time analysis to the target rna level

Quantitatively can use ABI to the target rna level by quantitative PCR in real time

7600, (PE-Applied Biosystems, Foster City CA) finish according to the specification sheets of manufacturers 7700 or 7900 sequence detection systems.Quantitatively the method for PCR in real time is well known in the art.

Before PCR in real time, isolating RNA is carried out ThermoScript II (RT) reaction, this reaction produces complementary DNA (cDNA), uses the substrate of this complementary DNA (cDNA) as the PCR in real time amplification then.Described RT and real-time PCR reactions carry out in same sample well in succession.(Carlsbad CA) obtains from Invitrogen for RT and PCR in real time reagent.RT, real-time PCR reactions are undertaken by well known to a person skilled in the art method.

The quantity of gene (or RNA) target that PCR in real time is obtained is used its expression level of expressing constant gene (such as GAPDH) or by using (CA) quantitatively total RNA comes stdn for Invetrogen, Inc.Carlsbad.Come quantitative GAPDH to express by PCR in real time, the quantitative and target while multichannel (multiplexing) of GAPDH is carried out, or carry out respectively.Use

RNA quantitative reagent (Invetrogen, Inc.Eugene, OR) quantitatively total RNA.With Carry out the RNA quantitative methods at Jones, (Analytical Biochemistry, 1998,265,368-374) middle instruction such as L.J..Use

4000 instruments (PE Applied Biosystems) are measured Fluorescence.

The probe and the primer of design and PCSK9 nucleic acid hybridization.The method that is used to design PCR in real time probe and primer is well known in the art, and can comprise that use is such as PRIMER

(Applied Biosystems, Foster City CA) wait software to software.

Protein level is analyzed

Antisense Suppression to PCSK9 nucleic acid can be assessed by measuring the PCSK9 protein level.The protein level of PCSK9 can be assessed or quantitatively by multiple mode well known in the art, described mode such as immunoprecipitation, Western engram analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA), quantitative protein assay method, protein active assay method (for example, Caspase activation measurement), immunohistochemistry, immunocytochemistry or fluorescence activated cell sorting (FACS).Antibody at target can be identified from multiple source and obtain, and described source such as MSRS antibody catalogue (AerieCorporation, Birmingham, MI); Perhaps can prepare by conventional monoclonal antibody well known in the art or polyclonal antibody generation method.The antibody that can be used for detecting people and P of Rats CSK9 is commercially available.

The body build-in test of antisense compounds

Testing antisense compounds (for example antisense oligonucleotide) in animal suppresses the expression of PCSK9 and produces the ability that phenotype changes (such as the minimizing of LDL-C) to assess them.Test can be carried out in intact animal, or carries out in experimental disease model.In order to use, antisense oligonucleotide is formulated in the pharmacy acceptable diluent, in phosphate buffered saline (PBS) to animal.Use and comprise using of parenteral path, such as intraperitoneal, intravenously and subcutaneous.The calculating of antisense oligonucleotide dosage and administration frequency and depends on that multiple factor is such as using path and the weight of animals within those skilled in the art's limit of power.After handling for some time, from the variation of different separate tissue RNA and measurement PCSK9 expression of nucleic acid with antisense oligonucleotide.Also can measure the variation of PCSK9 protein level.

Atherosclerotic animal model

Non-limiting open and carry stating and incorporate into

Embodiment hereinafter only is used to method, antisense oligonucleotide and the composition that is provided is provided, but not is intended to limit them.Each reference of putting down in writing among the application, Accession number etc. are all to carry the complete this paper of incorporating into of the mode of stating.

Embodiment

Embodiment 1: to the Antisense Suppression of people PCSK9:A549 cell

The antisense oligonucleotide of test target PCSK9 nucleic acid is in external effect to PCSK9mRNA.Will be in 96 orifice plates density be that the A549 cell of the cultivation of 4000 cells in every hole is handled with the antisense oligonucleotide of 60nM.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.The expression of PCSK9 has been represented at least 30% antisense oligonucleotide that suppresses to be displayed in Table 15.

What the motif hurdle showed is the wing-breach-wing motif of each antisense oligonucleotide.Antisense oligonucleotide is designed to 5-10-5 breach polymers, perhaps is 3-14-3 breach polymers, and wherein the breach section comprises 2 '-deoxynucleotide, and each pterion section comprises 2 '-MOE Nucleotide.As cited in the table 15, single nuclear base sequence can be by 5-10-5 motif and the representative of 3-14-3 motif.5 ' the Nucleotide of antisense oligonucleotide institute target on the GENBANK accession number shown in " 5 ' target site " is illustrated in.

Table 15: in people's cell (cell type A549) to the Antisense Suppression of PCSK9

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							395150	5	242	NM_174936.2	GAGGAGACCTAGAGGCCGTG	5-10-5	57
395151	6	300	NM_174936.2	AGGACCGCCTGGAGCTGACG	5-10-5	77
							395152	7	410	NM_174936.2	ACGCAAGGCTAGCACCAGCT	5-10-5	81
395153	9	480	NM_174936.2	CCTTGGCGCAGCGGTGGAAG	5-10-5	51
							395154	10	561	NM_174936.2	GGCGGGCAGTGCGCTCTGAC	5-10-5	40
395155	11	600	NM_174936.2	TGGTGAGGTATCCCCGGCGG	5-10-5	79
							395156	14	620	NM_174936.2	ATGGAAGACATGCAGGATCT	5-10-5	75
395157	15	646	NM_174936.2	TTCACCAGGAAGCCAGGAAG	5-10-5	72
							395158	17	705	NM_174936.2	CCTCGATGTAGTCGACATGG	5-10-5	61
395159	18	785	NM_174936.2	GTATTCATCCGCCCGGTACC	5-10-5	35
							395160	19	835	NM_174936.2	CTGGTGTCTAGGAGATACAC	5-10-5	47
395161	21	860	NM_174936.2	GATTTCCCGGTGGTCACTCT	5-10-5	70
							395162	24	890	NM_174936.2	CTCGAAGTCGGTGACCATGA	5-10-5	52
395163	25	923	NM_174936.2	GTGGAAGCGGGTCCCGTCCT	5-10-5	73
							395164	26	970	NM_174936.2	ACCCCTGCCAGGTGGGTGCC	5-10-5	69
395165	28	1004	NM_174936.2	ACCCTTGGCCACGCCGGCAT	5-10-5	81
							395166	29	1040	NM_174936.2	TTGGCAGTTGAGCACGCGCA	5-10-5	65
395167	31	1077	NM_174936.2	CCAGGCCTATGAGGGTGCCG	5-10-5	34
							395168	32	1098	NM_174936.2	GCTGGCTTTTCCGAATAAAC	5-10-5	69
395169	33	1210	NM_174936.2	GTGACCAGCACGACCCCAGC	5-10-5	61
							395171	34	1326	NM_174936.2	CCAAAGTCCCCAGGGTCACC	5-10-5	38
395173	36	1340	NM_174936.2	GCCAAAGTTGGTCCCCAAAG	5-10-5	64
							395174	38	1361	NM_174936.2	GGCAAAGAGGTCCACACAGC	5-10-5	72
395175	39	1389	NM_174936.2	TGGAGGCACCAATGATGTCC	5-10-5	41
							395177	45	1534	NM_174936.2	TTGGCAGAGAAGTGGATCAG	5-10-5	41
395178	50	1569	NM_174936.2	GGTCCTCAGGGAACCAGGCC	5-10-5	67
							395181	52	1640	NM_174936.2	AAACAGCTGCCAACCTGCCC	5-10-5	37
395182	54	1675	NM_174936.2	GTAGGCCCCGAGTGTGCTGA	5-10-5	51
							395183	57	1812	NM_174936.2	CGTTGTGGGCCCGGCAGACC	5-10-5	74
395184	58	1858	NM_174936.2	AGCAGGCAGCACCTGGCAAT	5-10-5	61
							395185	59	1920	NM_174936.2	CACGGGTCCCCATGCTGGCC	5-10-5	73
395186	60	2100	NM_174936.2	CTTTGCATTCCAGACCTGGG	5-10-5	83
							395187	62	2310	NM_174936.2	GGCAGCAGATGGCAACGGCT	5-10-5	80
395189	64	2504	NM_174936.2	TCAAGGGCCAGGCCAGCAGC	5-10-5	65
							395190	66	2597	NM_174936.2	ATGCCCCACAGTGAGGGAGG	5-10-5	60
395191	67	2606	NM_174936.2	AATGGTGAAATGCCCCACAG	5-10-5	76
							395193	68	2750	NM_174936.2	CATGGGAAGAATCCTGCCTC	5-10-5	48
395194	69	2832	NM_174936.2	GGAGATGAGGGCCATCAGCA	5-10-5	64
							395195	70	2900	NM_174936.2	TAGATGCCATCCAGAAAGCT	5-10-5	44
395196	72	2983	NM_174936.2	GGCATAGAGCAGAGTAAAGG	5-10-5	39
							395198	75	3437	NM_174936.2	GCTCAAGGAGGGACAGTTGT	5-10-5	73
395199	76	3472	NM_174936.2	AAAGATAAATGTCTGCTTGC	5-10-5	83
							395200	78	3543	NM_174936.2	TCTTCAAGTTACAAAAGCAA	5-10-5	40
395202	129	13816	NT_032977.8	GTGCCATCTGAACAGCACCT	5-10-5	36
							395203	110	13926	NT_032977.8	CCTGGAACCCCTGCAGCCAG	5-10-5	64
395204	152	13977	NT_032977.8	TTCAGGCAGGTTGCTGCTAG	5-10-5	55
							395206	136	14122	NT_032977.8	TAGGAGAAAGTAGGGAGAGC	5-10-5	45
395207	132	14179	NT_032977.8	TAAAAGCTGCAAGAGACTCA	5-10-5	49
							395208	139	14267	NT_032977.8	TCAGAGAAAACAGTCACCGA	5-10-5	56
395209	142	14404	NT_032977.8	TCATTTTAGAGACAGGAAGC	5-10-5	73
							395210	113	14441	NT_032977.8	GAATAACAGTGATGTCTGGC	5-10-5	82

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							395211	138	14494	NT_032977.8	TCACAGCTCACCGAGTCTGC	5-10-5	60
395212	98	14524	NT_032977.8	AGTGTAAAATAAAGCCCCTA	5-10-5	50
							395213	96	14601	NT_032977.8	AGGACCCAAGTCATCCTGCT	5-10-5	57
395214	124	14631	NT_032977.8	GGCCATCAGCTGGCAATGCT	5-10-5	50
							395215	133	14675	NT_032977.8	TAGACAAGGAAAGGGAGGCC	5-10-5	60
395216	103	14681	NT_032977.8	ATTTCATAGACAAGGAAAGG	5-10-5	51
							395218	146	1315	AK124635.1	TGACATTTGTGGGAGAGGAG	5-10-5	35
395220	104	2085	AK124635.1	CACAGTCCTGCAAAACAGCT	5-10-5	54
							395221	102	5590	NT_032977.8	ATGTGCAGAGATCAATCACA	5-10-5	69
395222	127	10633	NT_032977.8	GGTGGTAATTTGTCACAGCA	5-10-5	64
							395223	84	11308	NT_032977.8	AAGGTCACACAGTTAAGAGT	5-10-5	55
395226	147	24858	NT_032977.8	TGAGTTCATTTAAGAGTGGA	5-10-5	42
							399793	8	417	NM_174936.2	CCTCGGAACGCAAGGCTAGC	5-10-5	71
399794	12	606	NM_174936.2	GGATCTTGGTGAGGTATCCC	5-10-5	42
							399795	13	615	NM_174936.2	AGACATGCAGGATCTTGGTG	5-10-5	54
399796	16	651	NM_174936.2	TCATCTTCACCAGGAAGCCA	5-10-5	50
							399797	20	840	NM_174936.2	GTATGCTGGTGTCTAGGAGA	5-10-5	38
399798	22	866	NM_174936.2	GCCCTCGATTTCCCGGTGGT	5-10-5	54
							399799	23	880	NM_174936.2	GTGACCATGACCCTGCCCTC	5-10-5	75
399800	27	975	NM_174936.2	TGACCACCCCTGCCAGGTGG	5-10-5	67
							399801	30	1045	NM_174936.2	TTCCCTTGGCAGTTGAGCAC	5-10-5	79
399802	35	1335	NM_174936.2	AGTTGGTCCCCAAAGTCCCC	5-10-5	71
							399803	37	1352	NM_174936.2	GTCCACACAGCGGCCAAAGT	5-10-5	63
399804	40	1400	NM_174936.2	GCTGCAGTCGCTGGAGGCAC	5-10-5	46
							399805	41	1411	NM_174936.2	ACAAAGCAGGTGCTGCAGTC	5-10-5	46
399806	42	1470	NM_174936.2	GCATCATGGCTGCAATGCCA	5-10-5	85
							399807	43	1478	NM_174936.2	GGCAGACAGCATCATGGCTG	5-10-5	71
399808	44	1526	NM_174936.2	GAAGTGGATCAGTCTCTGCC	5-10-5	38
							399809	46	1539	NM_174936.2	CATCTTTGGCAGAGAAGTGG	5-10-5	53
399810	47	1545	NM_174936.2	TGATGACATCTTTGGCAGAG	5-10-5	63
							399811	48	1552	NM_174936.2	GCCTCATTGATGACATCTTT	5-10-5	61
399812	49	1564	NM_174936.2	TCAGGGAACCAGGCCTCATT	5-10-5	46
							399813	51	1583	NM_174936.2	GGTCAGTACCCGCTGGTCCT	5-10-5	72
399814	53	1645	NM_174936.2	CTGCAAAACAGCTGCCAACC	5-10-5	88
							399815	55	1740	NM_174936.2	AGAAACTGGAGCAGCTCAGC	5-10-5	38
399816	56	1746	NM_174936.2	TCCTGGAGAAACTGGAGCAG	5-10-5	51
							399817	61	2105	NM_174936.2	CTTGACTTTGCATTCCAGAC	5-10-5	84
399818	63	2415	NM_174936.2	AACCATTTTAAAGCTCAGCC	5-10-5	68
							399819	65	2509	NM_174936.2	CCCACTCAAGGGCCAGGCCA	5-10-5	87
399821	71	2906	NM_174936.2	TCTGGCTAGATGCCATCCAG	5-10-5	83
							399822	73	2988	NM_174936.2	AGCCTGGCATAGAGCAGAGT	5-10-5	70
399824	74	3233	NM_174936.2	AAGTAAGAAGAGGCTTGGCT	5-10-5	43
							399825	77	3477	NM_174936.2	ACCCAAAAGATAAATGTCTG	5-10-5	61
399827	100	13746	NT_032977.8	ATCTCAGGACAGGTGAGCAA	5-10-5	81
							399828	116	13760	NT_032977.8	GAGTAGAGATTCTCATCTCA	5-10-5	73
399829	117	13828	NT_032977.8	GAGTCTTCTGAAGTGCCATC	5-10-5	65
							399831	83	13986	NT_032977.8	AAGGAAGACTTCAGGCAGGT	5-10-5	52
399833	92	14397	NT_032977.8	AGAGACAGGAAGCTGCAGCT	5-10-5	54

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							399834	82	14670	NT_032977.8	AAGGAAAGGGAGGCCTAGAG	5-10-5	44
399836	130	2095	AK124635.1	GTGCTGACCACACAGTCCTG	5-10-5	96
							399837	107	3056	NT_032977.8	CCCACTATAATGGCAAGCCC	5-10-5	83
399838	80	4306	NT_032977.8	AACCCAGTTCTAATGCACCT	5-10-5	81
							399839	106	5140	NT_032977.8	CCAGTCAGAGTAGAACAGAG	5-10-5	68
399840	121	5599	NT_032977.8	GGAGCCTACATGTGCAGAGA	5-10-5	46
							399841	94	5667	NT_032977.8	AGCATGGCACCAGCATCTGC	5-10-5	59
399842	108	6652	NT_032977.8	CCCAGCCCTATCAGGAAGTG	5-10-5	67
							399843	144	7099	NT_032977.8	TGACATCCAGGAGGGAGGAG	5-10-5	33
399844	91	7556	NT_032977.8	AGACTGATGGAAGGCATTGA	5-10-5	56
							399845	131	7565	NT_032977.8	GTGTTGAGCAGACTGATGGA	5-10-5	48
399846	145	8836	NT_032977.8	TGACATCTTGTCTGGGAGCC	5-10-5	58
							399847	90	8948	NT_032977.8	AGACTAGGAGCCTGAGTTTT	5-10-5	38
399849	148	10252	NT_032977.8	TGGCAGCAACTCAGACATAT	5-10-5	74
							399851	88	12715	NT_032977.8	ACTGGATACATTGGCAGACA	5-10-5	62
399852	111	12928	NT_032977.8	CTAGAGGAACCACTAGATAT	5-10-5	66
							399854	97	16134	NT_032977.8	AGTCAAGCTGCTGCCCAGAG	5-10-5	82
399855	120	16668	NT_032977.8	GCTAGTTATTAAGCACCTGC	5-10-5	71
							399856	150	17267	NT_032977.8	TGTGAGCTCTGGCCCAGTGG	5-10-5	64
399857	115	18377	NT_032977.8	GAGTAAGGCAGGTTACTCTC	5-10-5	79
							399858	134	18408	NT_032977.8	TAGATGTGACTAACATTTAA	5-10-5	57
399859	105	19203	NT_032977.8	CACATTAGCCTTGCTCAAGT	5-10-5	75
							399860	151	19913	NT_032977.8	TGTGATGACCTGGAAAGGTG	5-10-5	36
399862	109	20188	NT_032977.8	CCCCTGCACAGAGCCTGGCA	5-10-5	59
							399863	141	20624	NT_032977.8	TCATGGCTGCAATGCCTGGT	5-10-5	46
399864	93	20995	NT_032977.8	AGAGAGGAGGGCTTAAAGAA	5-10-5	30
							399865	95	21082	NT_032977.8	AGCTGCCAACCTGCAAAAAG	5-10-5	75
399866	143	21481	NT_032977.8	TGAAAATCCATCCAGCACTG	5-10-5	74
							399867	89	21589	NT_032977.8	AGAACCATGGAGCACCTGAG	5-10-5	84
399868	123	21696	NT_032977.8	GGCACTGCCCTTCCACCAAA	5-10-5	53
							399869	118	24907	NT_032977.8	GCACCATCCAGACCAGAATC	5-10-5	49
399870	114	25413	NT_032977.8	GAGAGGTTCAGATCCAGGCC	5-10-5	66
							399871	4	135	NM_174936.2	GCGCGGAATCCTGGCTGGGA	3-14-3	40
399872	5	242	NM_174936.2	GAGGAGACCTAGAGGCCGTG	3-14-3	64
							399873	6	300	NM_174936.2	AGGACCGCCTGGAGCTGACG	3-14-3	65
399874	7	410	NM_174936.2	ACGCAAGGCTAGCACCAGCT	3-14-3	80
							399875	9	480	NM_174936.2	CCTTGGCGCAGCGGTGGAAG	3-14-3	67
399876	10	561	NM_174936.2	GGCGGGCAGTGCGCTCTGAC	3-14-3	62
							399877	11	600	NM_174936.2	TGGTGAGGTATCCCCGGCGG	3-14-3	73
399878	14	620	NM_174936.2	ATGGAAGACATGCAGGATCT	3-14-3	54
							399879	15	646	NM_174936.2	TTCACCAGGAAGCCAGGAAG	3-14-3	75
399880	17	705	NM_174936.2	CCTCGATGTAGTCGACATGG	3-14-3	80
							399881	18	785	NM_174936.2	GTATTCATCCGCCCGGTACC	3-14-3	63
399882	19	835	NM_174936.2	CTGGTGTCTAGGAGATACAC	3-14-3	66
							399883	21	860	NM_174936.2	GATTTCCCGGTGGTCACTCT	3-14-3	59
399884	24	890	NM_174936.2	CTCGAAGTCGGTGACCATGA	3-14-3	71
							399885	25	923	NM_174936.2	GTGGAAGCGGGTCCCGTCCT	3-14-3	73
399886	26	970	NM_174936.2	ACCCCTGCCAGGTGGGTGCC	3-14-3	76

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							399887	28	1004	NM_174936.2	ACCCTTGGCCACGCCGGCAT	3-14-3	54
399888	29	1040	NM_174936.2	TTGGCAGTTGAGCACGCGCA	3-14-3	75
							399889	31	1077	NM_174936.2	CCAGGCCTATGAGGGTGCCG	3-14-3	84
399890	32	1098	NM_174936.2	GCTGGCTTTTCCGAATAAAC	3-14-3	73
							399891	33	1210	NM_174936.2	GTGACCAGCACGACCCCAGC	3-14-3	99
399892	149	1297	NM_174936.2	TGGGCATTGGTGGCCCCAAC	3-14-3	61
							399893	34	1326	NM_174936.2	CCAAAGTCCCCAGGGTCACC	3-14-3	54
399894	128	1330	NM_174936.2	GTCCCCAAAGTCCCCAGGGT	3-14-3	80
							399895	36	1340	NM_174936.2	GCCAAAGTTGGTCCCCAAAG	3-14-3	82
399896	38	1361	NM_174936.2	GGCAAAGAGGTCCACACAGC	3-14-3	83
							399897	39	1389	NM_174936.2	TGGAGGCACCAATGATGTCC	3-14-3	70
399898	101	1465	NM_174936.2	ATGGCTGCAATGCCAGCCAC	3-14-3	37
							399899	45	1534	NM_174936.2	TTGGCAGAGAAGTGGATCAG	3-14-3	64
399900	50	1569	NM_174936.2	GGTCCTCAGGGAACCAGGCC	3-14-3	82
							399901	87	1576	NM_174936.2	ACCCGCTGGTCCTCAGGGAA	3-14-3	76
399902	119	1605	NM_174936.2	GCAGGGCGGCCACCAGGTTG	3-14-3	39
							399903	52	1640	NM_174936.2	AAACAGCTGCCAACCTGCCC	3-14-3	73
399904	54	1675	NM_174936.2	GTAGGCCCCGAGTGTGCTGA	3-14-3	81
							399905	57	1812	NM_174936.2	CGTTGTGGGCCCGGCAGACC	3-14-3	80
399906	58	1858	NM_174936.2	AGCAGGCAGCACCTGGCAAT	3-14-3	92
							399907	59	1920	NM_174936.2	CACGGGTCCCCATGCTGGCC	3-14-3	95
399908	60	2100	NM_174936.2	CTTTGCATTCCAGACCTGGG	3-14-3	84
							399909	62	2310	NM_174936.2	GGCAGCAGATGGCAACGGCT	3-14-3	73
399910	154	2410	NM 174936.2	TTTTAAAGCTCAGCCCCAGC	3-14-3	57
							399911	64	2504	NM_174936.2	TCAAGGGCCAGGCCAGCAGC	3-14-3	82
399912	66	2597	NM_174936.2	ATGCCCCACAGTGAGGGAGG	3-14-3	68
							399913	67	2606	NM_174936.2	AATGGTGAAATGCCCCACAG	3-14-3	92
399914	153	2649	NM_174936.2	TTGGGAGCAGCTGGCAGCAC	3-14-3	59
							399915	68	2750	NM_174936.2	CATGGGAAGAATCCTGCCTC	3-14-3	78
399916	69	2832	NM_174936.2	GGAGATGAGGGCCATCAGCA	3-14-3	71
							399917	70	2900	NM_174936.2	TAGATGCCATCCAGAAAGCT	3-14-3	81
399918	72	2983	NM_174936.2	GGCATAGAGCAGAGTAAAGG	3-14-3	82
							399919	112	3227	NM_174936.2	GAAGAGGCTTGGCTTCAGAG	3-14-3	57
399920	75	3437	NM_174936.2	GCTCAAGGAGGGACAGTTGT	3-14-3	84
							399921	76	3472	NM_174936.2	AAAGATAAATGTCTGCTTGC	3-14-3	78
399922	78	3543	NM_174936.2	TCTTCAAGTTACAAAAGCAA	3-14-3	61
							399923	85	13681	NT_032977.8	ACAAATTCCCAGACTCAGCA	3-14-3	82
399924	129	13816	NT_032977.8	GTGCCATCTGAACAGCACCT	3-14-3	84
							399925	110	13926	NT_032977.8	CCTGGAACCCCTGCAGCCAG	3-14-3	73
399926	152	13977	NT_032977.8	TTCAGGCAGGTTGCTGCTAG	3-14-3	47
							399927	140	13998	NT_032977.8	TCAGCCAGGCCAAAGGAAGA	3-14-3	78
399928	136	14122	NT_032977.8	TAGGAGAAAGTACGGAGAGC	3-14-3	47
							399929	132	14179	NT_032977.8	TAAAAGCTGCAAGAGACTCA	3-14-3	69
399930	139	14267	NT_032977.8	TCAGAGAAAACAGTCACCGA	3-14-3	82
							399931	142	14404	NT_032977.8	TCATTTTAGAGACAGGAAGC	3-14-3	79
399932	113	14441	NT_032977.8	GAATAACAGTGATGTCTGGC	3-14-3	83
							399933	138	14494	NT_032977.8	TCACAGCTCACCGAGTCTGC	3-14-3	78
399934	98	14524	NT_032977.8	AGTGTAAAATAAAGCCCCTA	3-14-3	79

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							399935	96	14601	NT_032977.8	AGGACCCAAGTCATCCTGCT	3-14-3	89
399936	124	14631	NT_032977.8	GGCCATCAGCTGGCAATGCT	3-14-3	70
							399937	133	14675	NT_032977.8	TAGACAAGGAAAGGGAGGCC	3-14-3	78
399938	103	14681	NT_032977.8	ATTTCATAGACAAGGAAAGG	3-14-3	67
							399940	146	1315	AK124635.1	TGACATTTGTGGGAGAGGAG	3-14-3	35
399942	104	2085	AK124635.1	CACAGTCCTGCAAAACAGCT	3-14-3	75
							399943	102	5590	NT_032977.8	ATGTGCAGAGATCAATCACA	3-14-3	64
399944	127	10633	NT_032977.8	GGTGGTAATTTGTCACAGCA	3-14-3	73
							399945	84	11308	NT_032977.8	AAGGTCACACAGTTAAGAGT	3-14-3	89
399947	126	22292	NT_032977.8	GGTGCATAAGGAGAAAGAGA	3-14-3	70
							399948	147	24858	NT_032977.8	TGAGTTCATTTAAGAGTGGA	3-14-3	46
399949	8	417	NM_174936.2	CCTCGGAACGCAAGGCTAGC	3-14-3	74
							399950	12	606	NM_174936.2	GGATCTTGGTGAGGTATCCC	3-14-3	68
399951	13	615	NM_174936.2	AGACATGCAGGATCTTGGTG	3-14-3	67
							399952	16	651	NM_174936.2	TCATCTTCACCAGGAAGCCA	3-14-3	74
399953	20	840	NM_174936.2	GTATGCTGGTGTCTAGGAGA	3-14-3	59
							399954	22	866	NM_174936.2	GCCCTCGATTTCCCGGTGGT	3-14-3	83
399955	23	880	NM_174936.2	GTGACCATGACCCTGCCCTC	3-14-3	62
							399956	27	975	NM_174936.2	TGACCACCCCTGCCAGGTGG	3-14-3	78
399957	30	1045	NM_174936.2	TTCCCTTGGCAGTTGAGCAC	3-14-3	82
							399958	35	1335	NM_174936.2	AGTTGGTCCCCAAAGTCCCC	3-14-3	78
399959	37	1352	NM_174936.2	GTCCACACAGCGGCCAAAGT	3-14-3	89
							399960	40	1400	NM_174936.2	GCTGCAGTCGCTGGAGGCAC	3-14-3	64
399961	41	1411	NM_174936.2	ACAAAGCAGGTGCTGCAGTC	3-14-3	63
							399962	42	1470	NM_174936.2	GCATCATGGCTGCAATGCCA	3-14-3	68
399963	43	1478	NM_174936.2	GGCAGACAGCATCATGGCTG	3-14-3	70
							399964	44	1526	NM_174936.2	GAAGTGGATCAGTCTCTGCC	3-14-3	70
399965	46	1539	NM_174936.2	CATCTTTGGCAGAGAAGTGG	3-14-3	49
							399966	47	1545	NM_174936.2	TGATGACATCTTTGGCAGAG	3-14-3	78
399967	48	1552	NM_174936.2	GCCTCATTGATGACATCTTT	3-14-3	82
							399968	49	1564	NM_174936.2	TCAGGGAACCAGGCCTCATT	3-14-3	71
399969	51	1583	NM_174936.2	GGTCAGTACCCGCTGGTCCT	3-14-3	82
							399970	53	1645	NM_174936.2	CTGCAAAACAGCTGCCAACC	3-14-3	74
399971	55	1740	NM_174936.2	AGAAACTGGAGCAGCTCAGC	3-14-3	48
							399972	56	1746	NM_174936.2	TCCTGGAGAAACTGGAGCAG	3-14-3	63
399973	61	2105	NM_174936.2	CTTGACTTTGCATTCCAGAC	3-14-3	74
							399974	63	2415	NM_174936.2	AACCATTTTAAAGCTCAGCC	3-14-3	71
399975	65	2509	NM_174936.2	CCCACTCAAGGGCCAGGCCA	3-14-3	91
							399976	122	2582	NM_174936.2	GGAGGGAGCTTCCTGGCACC	3-14-3	67
399977	71	2906	NM_174936.2	TCTGGCTAGATGCCATCCAG	3-14-3	89
							399978	73	2988	NM_174936.2	AGCCTGGCATAGAGCAGAGT	3-14-3	80
399979	135	2994	NM_174936.2	TAGCACAGCCTGGCATAGAG	3-14-3	83
							399980	74	3233	NM_174936.2	AAGTAAGAAGAGGCTTGGCT	3-14-3	50
399981	77	3477	NM_174936.2	ACCCAAAAGATAAATGTCTG	3-14-3	55
							399982	99	3550	NM_174936.2	ATAAATATCTTCAAGTTACA	3-14-3	36
399983	100	13746	NT_032977.8	ATCTCAGGACAGGTGAGCAA	3-14-3	96
							399984	116	13760	NT_032977.8	GAGTAGAGATTCTCATCTCA	3-14-3	71
399985	117	13828	NT_032977.8	GAGTCTTCTGAAGTGCCATC	3-14-3	76

Isis number	SEQ ID NO	5 ' target site	Target nucleic acid	Sequence	Motif	% suppresses
							399986	81	13903	NT_032977.8	AAGCAGGGCCTCAGGTGGAA	3-14-3	68
399987	83	13986	NT_032977.8	AAGGAAGACTTCAGGCAGGT	3-14-3	59
							399988	137	14112	NT_032977.8	TAGGGAGAGCTCACAGATGC	3-14-3	31
399989	92	14397	NT_032977.8	AGAGACAGGAAGCTGCAGCT	3-14-3	65
							399990	82	14670	NT_032977.8	AAGGAAAGGGAGGCCTAGAG	3-14-3	59
399992	130	2095	AK124635.1	GTGCTGACCACACAGTCCTG	3-14-3	94
							399993	107	3056	NT_032977.8	CCCACTATAATGGCAAGCCC	3-14-3	76
399994	80	4306	NT_032977.8	AACCCAGTTCTAATGCACCT	3-14-3	82
							399995	106	5140	NT_032977.8	CCAGTCAGAGTAGAACAGAG	3-14-3	74
399996	121	5599	NT_032977.8	GGAGCCTACATGTGCAGAGA	3-14-3	65
							399997	94	5667	NT_032977.8	AGCATGGCACCAGCATCTGC	3-14-3	77
399998	108	6652	NT_032977.8	CCCAGCCCTATCAGGAAGTG	3-14-3	78
							399999	144	7099	NT_032977.8	TGACATCCAGGAGGGAGGAG	3-14-3	43
400000	91	7556	NT_032977.8	AGACTGATGGAAGGCATTGA	3-14-3	84
							400001	131	7565	NT_032977.8	GTGTTGAGCAGACTGATGGA	3-14-3	73
400002	145	8836	NT_032977.8	TGACATCTTGTCTGGGAGCC	3-14-3	82
							400003	90	8948	NT_032977.8	AGACTAGGAGCCTGAGTTTT	3-14-3	48
400004	125	9099	NT_032977.8	GGCCTGCAGAAGCCAGAGAG	3-14-3	45
							400005	148	10252	NT_032977.8	TGGCAGCAACTCAGACATAT	3-14-3	73
400006	79	11472	NT_032977.8	AAATGCAGGGCTAAAATCAC	3-14-3	78
							400007	88	12715	NT_032977.8	ACTGGATACATTGGCAGACA	3-14-3	77
400008	111	12928	NT_032977.8	CTAGAGGAACCACTAGATAT	3-14-3	78
							400009	86	15471	NT_032977.8	ACAGCATTCTTGGTTAGGAG	3-14-3	73
400010	97	16134	NT_032977.8	AGTCAAGCTGCTGCCCAGAG	3-14-3	74
							400011	120	16668	NT_032977.8	GCTAGTTATTAAGCACCTGC	3-14-3	75
400012	150	17267	NT_032977.8	TGTGAGCTCTGGCCCAGTGG	3-14-3	64
							400013	115	18377	NT_032977.8	GAGTAAGGCAGGTTACTCTC	3-14-3	88
400014	134	18408	NT_032977.8	TAGATGTGACTAACATTTAA	3-14-3	58
							400015	105	19203	NT_032977.8	CACATTAGCCTTGCTCAAGT	3-14-3	89
400018	109	20188	NT_032977.8	CCCCTGCACAGAGCCTGGCA	3-14-3	62
							400019	141	20624	NT_032977.8	TCATGGCTGCAATGCCTGGT	3-14-3	47
400020	93	20995	NT_032977.8	AGAGAGGAGGGCTTAAAGAA	3-14-3	66
							400021	95	21082	NT_032977.8	AGCTGCCAACCTGCAAAAAG	3-14-3	61
400022	143	21481	NT_032977.8	TGAAAATCCATCCAGCACTG	3-14-3	90
							400023	89	21589	NT_032977.8	AGAACCATGGAGCACCTGAG	3-14-3	83
400024	123	21696	NT_032977.8	GGCACTGCCCTTCCACCAAA	3-14-3	79
							400025	118	24907	NT_032977.8	GCACCATCCAGACCAGAATC	3-14-3	78
400026	114	25413	NT_032977.8	GAGAGGTTCAGATCCAGGCC	3-14-3	81

Have following ISIS number antisense oligonucleotide and represented inhibition: 399806 PCSK9mRNA level at least 80%, 399814,399817,399819,399821,399827,399836,399837,399854,399867,399889,399891,399906,399907,399908,399913,399920,399924,399935,399945,399959,399975,399977,399983,399992,400000,400013,400015,400022 and 400023.The target area section of these antisense oligonucleotide targets is active target area sections.The target area of these antisense oligonucleotide targets is active target areas.

ISIS number 399814,399819,399836,399891,399906,399907,399913,399935,399945,399959,399975,399977,399983,399992,400013,400015 and 400022 inhibition that represented separately PCSK9mRNA level at least 85%.

ISIS number 399836,399891,399906,399907,399913,399975,399983,399992 and 400022 inhibition that represented separately PCSK9mRNA level at least 90%.

Embodiment 2: in the HepG2 cell to the Antisense Suppression of people PCSK9

The test antisense oligonucleotide suppresses the ability that PCSK9mRNA expresses in the HepG2 cell of cultivating.The HepG2 cell that with density in 96 orifice plates is the cultivation of 10000 cells in every hole is handled with the antisense oligonucleotide of 1500nM.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.

ISIS number

399819,395149,395150,395151,395152,395153,395154,395155,395156,395157,395158,395161,395162,395163,395164,395165,395166,395167,395168,395172,395173,395174,395178,395179,395182,395183,395185,395186,395187,395189,395190,395191,395193,395194,395195,395198,395199,395203,395207,395210,395211,395213,395214,395221,395222,399793,399794,399795,399798,399801,399803,399804,399806,399807,399812,399813,399814,399816,399817,399820,399821,399822,399823,399827,399828,399829,399833,399834,399836,399837,399841,399844,399846,399848,399849,399851,399852,399854,399855,399856,399857,399862,399865,399867,399868,399872,399873,399874,399875,399876,399877,399879,399880,399883,399884,399885,399886,399887,399888,399889,399890,399891,399892,399894,399895,399896,399900,399901,399902,399904,399905,399906,399907,399908,399909,399911,399912,399913,399915,399916,399918,399920,399921,399924,399925,399929,399931,399935,399936,399937,399943,399944,399945,399949,399950,399954,399957,399959,399960,399962,399963,399966,399967,399968,399969,399970,399972,399973,399975,399976,399977,399978,399979,399983,399984,399985,399986,399989,399990,399992,399996,399997,399998,400000,400001,400002,400004,400005,400007,400008,400009,400010,400012,400013,400015,400018,400021,400023,400024,400025 and 400026

All PCSK9 has been suppressed at least 70% separately in this experiment.The target area section of these antisense oligonucleotide targets is active target area sections.The target area of these antisense oligonucleotide targets is active target areas.

ISIS number

399819,395150,395152,395153,395154,395155,395156,395158,395163,395164,395165,395166,395167,395168,395173,395178,395183,395185,395186,395187,395189,395190,395193,395194,395199,395203,395210,395213,395214,399793,399798,399801,399804,399806,399813,399816,399820,399821,399822,399836,399849,399856,399857,399862,399868,399875,399877,399880,399885,399886,399887,399888,399889,399890,399894,399896,399900,399901,399904,399905,399906,399907,399911,399912,399916,399920,399925,399935,399936,399937,399945,399954,399957,399959,399960,399962,399968,399969,399973,399976,399977,399978,399989,399992,400002,400004,400007,400012,400013,400023 and 400024

All PCSK9 has been suppressed at least 80% separately in this experiment.

ISIS number

399819,395152,395153,395155,395156,395158,395163,395164,395165,395166,395168,395178,395183,395185,395187,395189,395190,395194,395199,395203,395214,399793,399804,399813,399821,399822,399836,399856,399868,399877,399887,399888,399890,399900,399904,399905,399907,399911,399912,399916,399925,399936,399954,399960,399962,399969,399976,399977,399978,399989,399992,400012,400013,400023 and 400024

All PCSK9 has been suppressed at least 85% separately in this experiment.

ISIS numbers 399819,395165,395183,395185,399868,399900,399907,399911,399912,399916,399936,399969 and 400024 has suppressed at least 90% with PCSK9 in this experiment separately.

Embodiment 3: to the Antisense Suppression of people PCSK9 (HepB3 cell)

The antisense oligonucleotide of test target PCSK9 nucleic acid is in external effect to PCSK9mRNA.The HepB3 cell that with density in 96 orifice plates is the cultivation of 4000 cells in every hole is handled with the antisense oligonucleotide of 75nM.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.Expression to PCSK9 has represented at least 30The antisense oligonucleotide that % suppresses shows in table 16,17 and 18.

What the motif hurdle showed is the wing-breach-wing motif of each antisense oligonucleotide.Antisense oligonucleotide is designed to 5-10-5 breach polymers, perhaps is 3-14-3 breach polymers, perhaps is 2-13-5 breach polymers, and wherein the breach section comprises 2 '-deoxynucleotide, and each pterion section comprises 2 '-MOE Nucleotide.As cited in the table 16,17 and 18, single nuclear base sequence can be by 5-10-5 motif and 3-14-3 motif and the representative of 2-13-5 motif.5 ' the Nucleotide of antisense oligonucleotide institute target on the GENBANK accession number shown in " 5 ' target site " is illustrated in.

Table 16: the Antisense Suppression of target SEQ ID NO:1 in people's cell (HepB3) to PCSK9

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410742	294	313	GCCTGGAGCTGACGGTGCCC	5-10-5	75.1	159
405999	298	317	GACCGCCTGGAGCTGACGGT	5-10-5	70.3	160
							395151	300	319	AGGACCGCCTGGAGCTGACG	5-10-5	57.3	6
405861	406	425	AAGGCTAGCACCAGCTCCTC	5-10-5	90.5	162
							405862	407	426	CAAGGCTAGCACCAGCTCCT	5-10-5	92.3	163
405863	408	427	GCAAGGCTAGCACCAGCTCC	5-10-5	82.6	164
							405864	409	428	CGCAAGGCTAGCACCAGCTC	5-10-5	91.8	165
395152	410	429	ACGCAAGGCTAGCACCAGCT	5-10-5	93.3	7
							405865	411	430	AACGCAAGGCTAGCACCAGC	5-10-5	84.6	166
405866	412	431	GAACGCAAGGCTAGCACCAG	5-10-5	81.8	167
							405867	413	432	GGAACGCAAGGCTAGCACCA	5-10-5	74.0	168
405868	414	433	CGGAACGCAAGGCTAGCACC	5-10-5	76.8	169
							399793	417	436	CCTCGGAACGCAAGGCTAGC	5-10-5	77.9	8
410743	421	440	TCCTCCTCGGAACGCAAGGC	5-10-5	76.7	170
							410744	446	465	GTGCTCGGGTGCTTCGGCCA	5-10-5	76.9	171
410745	466	485	TGGAAGGTGGCTGTGGTTCC	5-10-5	41.7	172
							395153	480	499	CCTTGGCGCAGCGGTGGAAG	5-10-5	81.1	9
406000	482	501	ATCCTTGGCGCAGCGGTGGA	5-10-5	79.1	173
							406001	484	503	GGATCCTTGGCGCAGCGGTG	5-10-5	63.1	174
406002	488	507	CCACGGATCCTTGGCGCAGC	5-10-5	80.8	175
							410746	507	526	CGTAGGTGCCAGGCAACCTC	5-10-5	44.8	176
410747	545	564	TGACTGCGAGAGGTGGGTCT	5-10-5	NA	177
							406003	555	574	CAGTGCGCTCTGACTGCGAG	5-10-5	84.2	178
406004	557	576	GGCAGTGCGCTCTGACTGCG	5-10-5	56.4	179
							406005	559	578	CGGGCAGTGCGCTCTGACTG	5-10-5	83.4	180
406006	562	581	CGGCGGGCAGTGCGCTCTGA	5-10-5	71.0	181
							410748	591	610	ATCCCCGGCGGGCAGCCTGG	5-10-5	56.0	182
406007	595	614	AGGTATCCCCGGCGGGCAGC	5-10-5	76.3	183
							410574	597	616	TGAGGTATCCCCGGCGGGCA	3-14-3	69.1	184
410529	597	616	TGAGGTATCCCCGGCGGGCA	5-10-5	77.4	184
							410647	597	616	TGAGGTATCCCCGGCGGGCA	2-13-5	90.7	184
410575	598	617	GTGAGGTATCCCCGGCGGGC	3-14-3	71.5	185
							410648	598	617	GTGAGGTATCCCCGGCGGGC	2-13-5	82.8	185
410530	598	617	GTGAGGTATCCCCGGCGGGC	5-10-5	83.2	185
							410649	599	618	GGTGAGGTATCCCCGGCGGG	2-13-5	53.5	186
410576	599	618	GGTGAGGTATCCCCGGCGGG	3-14-3	56.2	186
							410531	599	618	GGTGAGGTATCCCCGGCGGG	5-10-5	63.6	186
410650	600	619	TGGTGAGGTATCCCCGGCGG	2-13-5	86.1	11
							399877	600	619	TGGTGAGGTATCCCCGGCGG	3-14-3	92.6	11

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							395155	600	619	TGGTGAGGTATCCCCGGCGG	5-10-5	92.7	11
410577	601	620	TTGGTGAGGTATCCCCGGCG	3-14-3	62.4	187
							410532	601	620	TTGGTGAGGTATCCCCGGCG	5-10-5	63.5	187
410651	601	620	TTGGTGAGGTATCCCCGGCG	2-13-5	75.5	187
							410652	602	621	CTTGGTGAGGTATCCCCGGC	2-13-5	81.2	188
410578	602	621	CTTGGTGAGGTATCCCCGGC	3-14-3	83.3	188
							406008	602	621	CTTGGTGAGGTATCCCCGGC	5-10-5	95.2	188
410653	603	622	TCTTGGTGAGGTATCCCCGG	2-13-5	68.9	189
							410579	603	622	TCTTGGTGAGGTATCCCCGG	3-14-3	74.0	189
410533	603	622	TCTTGGTGAGGTATCCCCGG	5-10-5	79.0	189
							410580	604	623	ATCTTGGTGAGGTATCCCCG	3-14-3	62.3	190
410654	604	623	ATCTTGGTGAGGTATCCCCG	2-13-5	65.2	190
							406009	604	623	ATCTTGGTGAGGTATCCCCG	5-10-5	90.7	190
410534	605	624	GATCTTGGTGAGGTATCCCC	5-10-5	59.8	191
							410581	605	624	GATCTTGGTGAGGTATCCCC	3-14-3	72.9	191
410655	605	624	GATCTTGGTGAGGTATCCCC	2-13-5	77.4	191
							399794	606	625	GGATCTTGGTGAGGTATCCC	5-10-5	56.5	12
410656	606	625	GGATCTTGGTGAGGTATCCC	2-13-5	68.0	12
							399950	606	625	GGATCTTGGTGAGGTATCCC	3-14-3	74.4	12
410535	607	626	AGGATCTTGGTGAGGTATCC	5-10-5	65.7	192
							410582	607	626	AGGATCTTGGTGAGGTATCC	3-14-3	69.5	192
410657	607	626	AGGATCTTGGTGAGGTATCC	2-13-5	73.1	192
							406010	609	628	GCAGGATCTTGGTGAGGTAT	5-10-5	56.9	193
406011	611	630	ATGCAGGATCTTGGTGAGGT	5-10-5	70.7	194
							406012	613	632	ACATGCAGGATCTTGGTGAG	5-10-5	69.1	195
406013	617	636	GAAGACATGCAGGATCTTGG	5-10-5	77.4	196
							395156	620	639	ATGGAAGACATGCAGGATCT	5-10-5	76.7	14
410749	628	647	AGAAGGCCATGGAAGACATG	5-10-5	59.4	197
							410750	638	657	GAAGCCAGGAAGAAGGCCAT	5-10-5	57.5	198
399879	646	665	TTCACCAGGAAGCCAGGAAG	3-14-3	91.9	15
							406014	648	667	TCTTCACCAGGAAGCCAGGA	5-10-5	94.0	199
406015	653	672	ACTCATCTTCACCAGGAAGC	5-10-5	78.8	200
							406016	655	674	CCACTCATCTTCACCAGGAA	5-10-5	87.2	201
410730	657	676	CGCCACTCATCTTCACCAGG	5-10-5	85.4	202
							406017	659	678	GTCGCCACTCATCTTCACCA	5-10-5	76.3	203
406018	661	680	AGGTCGCCACTCATCTTCAC	5-10-5	63.2	204
							406019	663	682	GCAGGTCGCCACTCATCTTC	5-10-5	68.1	205
406020	665	684	CAGCAGGTCGCCACTCATCT	5-10-5	83.7	206
							410731	667	686	TCCAGCAGGTCGCCACTCAT	5-10-5	72.9	207
410751	685	704	GGCAACTTCAAGGCCAGCTC	5-10-5	84.6	208
							395158	705	724	CCTCGATGTAGTCGACATGG	5-10-5	93.9	17
410752	724	743	GCAAAGACAGAGGAGTCCTC	5-10-5	76.3	209
							406021	782	801	TTCATCCGCCCGGTACCGTG	5-10-5	79.6	210
406022	784	803	TATTCATCCGCCCGGTACCG	5-10-5	78.7	211
							406023	787	806	TGGTATTCATCCGCCCGGTA	5-10-5	92.5	212
406024	789	808	GCTGGTATTCATCCGCCCGG	5-10-5	69.7	213
							410732	791	810	GGGCTGGTATTCATCCGCCC	5-10-5	30.4	214
410753	821	840	ATACACCTCCACCAGGCTGC	5-10-5	72.8	215
							406025	832	851	GTGTCTAGGAGATACACCTC	5-10-5	74.2	216
406026	837	856	TGCTGGTGTCTAGGAGATAC	5-10-5	80.5	217
							405869	862	881	TCGATTTCCCGGTGGTCACT	5-10-5	87.6	218
405870	863	882	CTCGATTTCCCGGTGGTCAC	5-10-5	83.3	219
							405871	864	883	CCTCGATTTCCCGGTGGTCA	5-10-5	87.0	220

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405872	865	884	CCCTCGATTTCCCGGTGGTC	5-10-5	88.2	221
399798	866	885	GCCCTCGATTTCCCGGTGGT	5-10-5	84.3	22
							399954	866	885	GCCCTCGATTTCCCGGTGGT	3-14-3	90.3	22
405873	867	886	TGCCCTCGATTTCCCGGTGG	5-10-5	90.0	222
							405874	868	887	CTGCCCTCGATTTCCCGGTG	5-10-5	91.4	223
405875	869	888	CCTGCCCTCGATTTCCCGGT	5-10-5	93.5	224
							405876	870	889	CCCTGCCCTCGATTTCCCGG	5-10-5	90.1	225
406027	874	893	ATGACCCTGCCCTCGATTTC	5-10-5	73.9	226
							406028	876	895	CCATGACCCTGCCCTCGATT	5-10-5	92.3	227
406029	878	897	GACCATGACCCTGCCCTCGA	5-10-5	91.4	228
							406030	882	901	CGGTGACCATGACCCTGCCC	5-10-5	95.6	229
406031	884	903	GTCGGTGACCATGACCCTGC	5-10-5	89.6	230
							410733	886	905	AAGTCGGTGACCATGACCCT	5-10-5	65.7	231
406032	888	907	CGAAGTCGGTGACCATGACC	5-10-5	88.5	232
							410754	898	917	GGCACATICTCGAAGTCGGT	5-10-5	80.1	233
395163	923	942	GTGGAAGCGGGTCCCGTCCT	5-10-5	83.9	25
							410755	933	952	TGGCCTGTCTGTGGAAGCGG	5-10-5	NA	234
410756	960	979	GGTGGGTGCCATGACTGTCA	5-10-5	67.1	235
							406033	967	986	CCTGCCAGGTGGGTGCCATG	5-10-5	91.2	237
406034	972	991	CCACCCCTGCCAGGTGGGTG	5-10-5	59.3	238
							406035	977	996	GCTGACCACCCCTGCCAGGT	5-10-5	91.7	239
410757	985	1004	TCCCGGCCGCTGACCACCCC	5-10-5	88.9	240
							406036	989	1008	GGCATCCCGGCCGCTGACCA	5-10-5	84.0	241
406037	992	1011	GCCGGCATCCCGGCCGCTGA	5-10-5	55.9	242
							410536	997	1016	GCCACGCCGGCATCCCGGCC	5-10-5	63.7	243
410658	997	1016	GCCACGCCGGCATCCCGGCC	2-13-5	82.0	243
							410583	997	1016	GCCACGCCGGCATCCCGGCC	3-14-3	87.3	243
410537	998	1017	GGCCACGCCGGCATCCCGGC	5-10-5	58.5	244
							410659	998	1017	GGCCACGCCGGCATCCCGGC	2-13-5	73.7	244
410584	998	1017	GGCCACGCCGGCATCCCGGC	3-14-3	79.5	244
							410660	999	1018	TGGCCACGCCGGCATCCCGG	2-13-5	63.0	245
410585	999	1018	TGGCCACGCCGGCATCCCGG	3-14-3	73.2	245
							406038	999	1018	TGGCCACGCCGGCATCCCGG	5-10-5	86.3	245
410661	1000	1019	TTGGCCACGCCGGCATCCCG	2-13-5	53.3	246
							410586	1000	1019	TTGGCCACGCCGGCATCCCG	3-14-3	60.3	246
405877	1000	1019	TTGGCCACGCCGGCATCCCG	5-10-5	83.2	246
							410587	1001	1020	CTTGGCCACGCCGGCATCCC	3-14-3	63.2	247
410662	1001	1020	CTTGGCCACGCCGGCATCCC	2-13-5	67.3	247
							405878	1001	1020	CTTGGCCACGCCGGCATCCC	5-10-5	91.4	247
410588	1002	1021	CCTTGGCCACGCCGGCATCC	3-14-3	65.3	248
							410663	1002	1021	CCTTGGCCACGCCGGCATCC	2-13-5	67.9	248
405879	1002	1021	CCTTGGCCACGCCGGCATCC	5-10-5	94.1	248
							410589	1003	1022	CCCTTGGCCACGCCGGCATC	3-14-3	80.1	249
410664	1003	1022	CCCTTGGCCACGCCGGCATC	2-13-5	81.9	249
							405880	1003	1022	CCCTTGGCCACGCCGGCATC	5-10-5	93.5	249
410665	1004	1023	ACCCTTGGCCACGCCGGCAT	2-13-5	78.7	28
							399887	1004	1023	ACCCTTGGCCACGCCGGCAT	3-14-3	91.9	28
395165	1004	1023	ACCCTTGGCCACGCCGGCAT	5-10-5	96.7	28
							410590	1005	1024	CACCCTTGGCCACGCCGGCA	3-14-3	82.2	250
410666	1005	1024	CACCCTTGGCCACGCCGGCA	2-13-5	82.7	250
							405881	1005	1024	CACCCTTGGCCACGCCGGCA	5-10-5	98.3	250
410667	1006	1025	GCACCCTTGGCCACGCCGGC	2-13-5	84.7	251
							410591	1006	1025	GCACCCTTGGCCACGCCGGC	3-14-3	86.3	251

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405882	1006	1025	GCACCCTTGGCCACGCCGGC	5-10-5	91.6	251
410668	1007	1026	GGCACCCTTGGCCACGCCGG	2-13-5	91.4	252
							405883	1007	1026	GGCACCCTTGGCCACGCCGG	5-10-5	92.5	252
410592	1007	1026	GGCACCCTTGGCCACGCCGG	3-14-3	93.4	252
							410669	1008	1027	TGGCACCCTTGGCCACGCCG	2-13-5	69.0	253
410593	1008	1027	TGGCACCCTTGGCCACGCCG	3-14-3	88.8	253
							405884	1008	1027	TGGCACCCTTGGCCACGCCG	5-10-5	90.8	253
410670	1009	1028	CTGGCACCCTTGGCCACGCC	2-13-5	74.9	254
							410594	1009	1028	CTGGCACCCTTGGCCACGCC	3-14-3	75.2	254
410538	1009	1028	CTGGCACCCTTGGCCACGCC	5-10-5	78.2	254
							410539	1010	1029	GCTGGCACCCTTGGCCACGC	5-10-5	61.9	255
410595	1010	1029	GCTGGCACCCTTGGCCACGC	3-14-3	83.1	255
							410671	1010	1029	GCTGGCACCCTTGGCCACGC	2-13-5	83.3	255
410758	1015	1034	CGCATGCTGGCACCCTTGGC	5-10-5	73.6	256
							406039	1036	1055	CAGTTGAGCACGCGCAGGCT	5-10-5	91.2	257
406040	1038	1057	GGCAGTTGAGCACGCGCAGG	5-10-5	96.5	258
							399888	1040	1059	TTGGCAGTTGAGCACGCGCA	3-14-3	90.9	29
395166	1040	1059	TTGGCAGTTGAGCACGCGCA	5-10-5	96.2	29
							406041	1042	1061	CCTTGGCAGTTGAGCACGCG	5-10-5	96.6	259
399801	1045	1064	TTCCCTTGGCAGTTGAGCAC	5-10-5	95.6	30
							406042	1047	1066	CCTTCCCTTGGCAGTTGAGC	5-10-5	92.0	260
406043	1051	1070	GTGCCCTTCCCTTGGCAGTT	5-10-5	91.9	261
							406044	1053	1072	CCGTGCCCTTCCCTTGGCAG	5-10-5	95.4	262
410759	1064	1083	GGTGCCGCTAACCGTGCCCT	5-10-5	83.7	263
							410760	1088	1107	CCGAATAAACTCCAGGCCTA	5-10-5	96.7	265
406045	1096	1115	TGGCTTTTCCGAATAAACTC	5-10-5	88.4	266
							395168	1098	1117	GCTGGCTTTTCCGAATAAAC	5-10-5	91.9	32
405909	1100	1119	CAGCTGGCTTTTCCGAATAA	5-10-5	80.3	267
							405910	1102	1121	ACCAGCTGGCTTTTCCGAAT	5-10-5	90.9	268
405911	1104	1123	GGACCAGCTGGCTTTTCCGA	5-10-5	88.0	269
							405912	1108	1127	GGCTGGACCAGCTGGCTTTT	5-10-5	78.2	270
410761	1119	1138	GTGGCCCCACAGGCTGGACC	5-10-5	53.7	271
							410762	1132	1151	AGCAGCACCACCAGTGGCCC	5-10-5	57.6	272
410763	1154	1173	GCTGTACCCACCCGCCAGGG	5-10-5	68.8	273
							410764	1200	1219	CGACCCCAGCCCTCGCCAGG	5-10-5	66.3	274
399891	1210	1229	GTGACCAGCACGACCCCAGC	3-14-3	91.1	33
							405913	1212	1231	CGGTGACCAGCACGACCCCA	5-10-5	93.8	275
405914	1214	1233	AGCGGTGACCAGCACGACCC	5-10-5	90.4	276
							405915	1216	1235	GCAGCGGTGACCAGCACGAC	5-10-5	86.8	277
405916	1218	1237	CGGCAGCGGTGACCAGCACG	5-10-5	91.3	278
							410734	1219	1238	CCGGCAGCGGTGACCAGCAC	5-10-5	65.8	279
405917	1222	1241	TTGCCGGCAGCGGTGACCAG	5-10-5	62.0	280
							405918	1224	1243	AGTTGCCGGCAGCGGTGACC	5-10-5	33.5	281
405919	1226	1245	GAAGTTGCCGGCAGCGGTGA	5-10-5	68.2	282
							405920	1228	1247	CGGAAGTTGCCGGCAGCGGT	5-10-5	86.2	283
405921	1230	1249	CCCGGAAGTTGCCGGCAGCG	5-10-5	85.5	284
							405922	1232	1251	GTCCCGGAAGTTGCCGGCAG	5-10-5	86.0	285
410765	1273	1292	ATGACCTCGGGAGCTGAGGC	5-10-5	50.4	286
							410766	1283	1302	CCCAACTGTGATGACCTCGG	5-10-5	70.6	287
405923	1295	1314	GGCATTGGTGGCCCCAACTG	5-10-5	94.3	288
							410767	1305	1324	GCTGGTCTTGGGCATTGGTG	5-10-5	65.1	289
405924	1318	1337	CCCAGGGTCACCGGCTGGTC	5-10-5	93.1	290
							410735	1320	1339	TCCCCAGGGTCACCGGCTGG	5-10-5	78.1	291

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405925	1322	1341	AGTCCCCAGGGTCACCGGCT	5-10-5	93.5	292
405926	1324	1343	AAAGTCCCCAGGGTCACCGG	5-10-5	94.6	293
							405927	1328	1347	CCCCAAAGTCCCCAGGGTCA	5-10-5	94.5	294
405928	1333	1352	TTGGTCCCCAAAGTCCCCAG	5-10-5	90.0	295
							405929	1337	1356	AAAGTTGGTCCCCAAAGTCC	5-10-5	85.5	296
399895	1340	1359	GCCAAAGTTGGTCCCCAAAG	3-14-3	84.6	36
							395173	1340	1359	GCCAAAGTTGGTCCCCAAAG	5-10-5	94.8	36
405930	1342	1361	CGGCCAAAGTTGGTCCCCAA	5-10-5	92.9	297
							405931	1344	1363	AGCGGCCAAAGTTGGTCCCC	5-10-5	88.8	298
405932	1346	1365	ACAGCGGCCAAAGTTGGTCC	5-10-5	90.6	299
							405933	1348	1367	ACACAGCGGCCAAAGTTGGT	5-10-5	NA	300
405934	1350	1369	CCACACAGCGGCCAAAGTTG	5-10-5	92.7	301
							405935	1354	1373	AGGTCCACACAGCGGCCAAA	5-10-5	86.0	302
410736	1356	1375	AGAGGTCCACACAGCGGCCA	5-10-5	73.8	303
							405936	1358	1377	AAAGAGGTCCACACAGCGGC	5-10-5	93.9	304
410768	1380	1399	CAATGATGTCCTCCCCTGGG	5-10-5	79.7	305
							405937	1387	1406	GAGGCACCAATGATGTCCTC	5-10-5	77.7	306
405938	1391	1410	GCTGGAGGCACCAATGATGT	5-10-5	75.5	307
							405939	1393	1412	TCGCTGGAGGCACCAATGAT	5-10-5	70.6	308
405940	1395	1414	AGTCGCTGGAGGCACCAATG	5-10-5	84.4	309
							405941	1397	1416	GCAGTCGCTGGAGGCACCAA	5-10-5	90.1	310
399804	1400	1419	GCTGCAGTCGCTGGAGGCAC	5-10-5	80.8	40
							399960	1400	1419	GCTGCAGTCGCTGGAGGCAC	3-14-3	82.4	40
405942	1402	1421	GTGCTGCAGTCGCTGGAGGC	5-10-5	69.8	311
							405943	1404	1423	AGGTGCTGCAGTCGCTGGAG	5-10-5	83.6	312
410737	1406	1425	GCAGGTGCTGCAGTCGCTGG	5-10-5	49.8	313
							405944	1407	1426	AGCAGGTGCTGCAGTCGCTG	5-10-5	80.7	314
405945	1409	1428	AAAGCAGGTGCTGCAGTCGC	5-10-5	41.1	315
							405946	1413	1432	ACACAAAGCAGGTGCTGCAG	5-10-5	70.4	316
405947	1415	1434	TGACACAAAGCAGGTGCTGC	5-10-5	72.5	317
							410769	1425	1444	TCCCACTCTGTGACACAAAG	5-10-5	84.9	318
405948	1467	1486	TCATGGCTGCAATGCCAGCC	5-10-5	45.9	319
							399806	1470	1489	GCATCATGGCTGCAATGCCA	5-10-5	82.8	42
399962	1470	1489	GCATCATGGCTGCAATGCCA	3-14-3	86.1	42
							405949	1472	1491	CAGCATCATGGCTGCAATGC	5-10-5	84.9	320
405950	1474	1493	GACAGCATCATGGCTGCAAT	5-10-5	76.9	321
							405951	1476	1495	CAGACAGCATCATGGCTGCA	5-10-5	75.4	322
405952	1480	1499	TCGGCAGACAGCATCATGGC	5-10-5	85.1	323
							410738	1482	1501	GCTCGGCAGACAGCATCATG	5-10-5	68.4	324
405953	1484	1503	CGGCTCGGCAGACAGCATCA	5-10-5	93.6	325
							405954	1486	1505	TCCGGCTCGGCAGACAGCAT	5-10-5	87.5	326
410770	1500	1519	CGGCCAGGGTGAGCTCCGGC	5-10-5	68.5	327
							405955	1513	1532	CTCTGCCTCAACTCGGCCAG	5-10-5	94.2	328
405956	1515	1534	GTCTCTGCCTCAACTCGGCC	5-10-5	94.3	329
							405958	1519	1538	ATCAGTCTCTGCCTCAACTC	5-10-5	80.3	331
405959	1521	1540	GGATCAGTCTCTGCCTCAAC	5-10-5	95.4	332
							405960	1523	1542	GTGGATCAGTCTCTGCCTCA	5-10-5	90.1	333
405961	1525	1544	AAGTGGATCAGTCTCTGCCT	5-10-5	88.8	334
							405962	1528	1547	GAGAAGTGGATCAGTCTCTG	5-10-5	56.1	335
410739	1530	1549	CAGAGAAGTGGATCAGTCTC	5-10-5	NA	336
							405963	1532	1551	GGCAGAGAAGTGGATCAGTC	5-10-5	59.7	337
405964	1536	1555	CTTTGGCAGAGAAGTGGATC	5-10-5	45.3	338
							405965	1541	1560	GACATCTTTGGCAGAGAAGT	5-10-5	55.9	339

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405966	1543	1562	ATGACATCTTTGGCAGAGAA	5-10-5	51.3	340
405967	1547	1566	ATTGATGACATCTTTGGCAG	5-10-5	64.4	341
							405968	1549	1568	TCATTGATGACATCTTTGGC	5-10-5	74.6	342
399967	1552	1571	GCCTCATTGATGACATCTTT	3-14-3	80.1	48
							405969	1554	1573	AGGCCTCATTGATGACATCT	5-10-5	63.0	343
405970	1556	1575	CCAGGCCTCATTGATGACAT	5-10-5	66.8	344
							410740	1558	1577	AACCAGGCCTCATTGATGAC	5-10-5	46.8	345
405885	1560	1579	GGAACCAGGCCTCATTGATG	5-10-5	73.4	346
							410596	1562	1581	AGGGAACCAGGCCTCATTGA	3-14-3	NA	348
410672	1562	1581	AGGGAACCAGGCCTCATTGA	2-13-5	NA	348
							405887	1562	1581	AGGGAACCAGGCCTCATTGA	5-10-5	NA	348
410597	1563	1582	CAGGGAACCAGGCCTCATTG	3-14-3	NA	349
							405888	1563	1582	CAGGGAACCAGGCCTCATTG	5-10-5	NA	349
410673	1563	1582	CAGGGAACCAGGCCTCATTG	2-13-5	NA	349
							410674	1564	1583	TCAGGGAACCAGGCCTCATT	2-13-5	60.7	49
399812	1564	1583	TCAGGGAACCAGGCCTCATT	5-10-5	68.7	49
							399968	1564	1583	TCAGGGAACCAGGCCTCATT	3-14-3	84.5	49
410598	1565	1584	CTCAGGGAACCAGGCCTCAT	3-14-3	74.5	350
							410675	1565	1584	CTCAGGGAACCAGGCCTCAT	2-13-5	76.9	350
405889	1565	1584	CTCAGGGAACCAGGCCTCAT	5-10-5	80.2	350
							410599	1566	1585	CCTCAGGGAACCAGGCCTCA	3-14-3	70.6	351
410676	1566	1585	CCTCAGGGAACCAGGCCTCA	2-13-5	77.8	351
							405890	1566	1585	CCTCAGGGAACCAGGCCTCA	5-10-5	87.7	351
410600	1567	1586	TCCTCAGGGAACCAGGCCTC	3-14-3	76.5	352
							410677	1567	1586	TCCTCAGGGAACCAGGCCTC	2-13-5	88.4	352
405891	1567	1586	TCCTCAGGGAACCAGGCCTC	5-10-5	96.1	352
							405892	1568	1587	GTCCTCAGGGAACCAGGCCT	5-10-5	71.4	353
410601	1568	1587	GTCCTCAGGGAACCAGGCCT	3-14-3	72.7	353
							410678	1568	1587	GTCCTCAGGGAACCAGGCCT	2-13-5	75.0	353
395178	1569	1588	GGTCCTCAGGGAACCAGGCC	5-10-5	76.7	50
							410679	1569	1588	GGTCCTCAGGGAACCAGGCC	2-13-5	77.6	50
399900	1569	1588	GGTCCTCAGGGAACCAGGCC	3-14-3	92.0	50
							408653	1570	1589	TGGTCCTCAGGGAACCAGGC	5-10-5	42.5	354
410602	1570	1589	TGGTCCTCAGGGAACCAGGC	3-14-3	66.5	354
							410680	1570	1589	TGGTCCTCAGGGAACCAGGC	2-13-5	71.6	354
410603	1571	1590	CTGGTCCTCAGGGAACCAGG	3-14-3	40.8	355
							410681	1571	1590	CTGGTCCTCAGGGAACCAGG	2-13-5	44.4	355
405971	1571	1590	CTGGTCCTCAGGGAACCAGG	5-10-5	65.5	355
							410540	1572	1591	GCTGGTCCTCAGGGAACCAG	5-10-5	50.9	356
410682	1572	1591	GCTGGTCCTCAGGGAACCAG	2-13-5	54.1	356
							410604	1572	1591	GCTGGTCCTCAGGGAACCAG	3-14-3	62.5	356
405972	1573	1592	CGCTGGTCCTCAGGGAACCA	5-10-5	77.6	357
							405973	1578	1597	GTACCCGCTGGTCCTCAGGG	5-10-5	83.8	358
405974	1580	1599	CAGTACCCGCTGGTCCTCAG	5-10-5	89.0	359
							399813	1583	1602	GGTCAGTACCCGCTGGTCCT	5-10-5	72.4	51
399969	1583	1602	GGTCAGTACCCGCTGGTCCT	3-14-3	93.4	51
							410771	1628	1647	ACCTGCCCCATGGGTGCTGG	5-10-5	NA	360
395181	1640	1659	AAACAGCTGCCAACCTGCCC	5-10-5	87.5	52
							405975	1642	1661	CAAAACAGCTGCCAACCTGC	5-10-5	77.4	361
405976	1647	1666	TCCTGCAAAACAGCTGCCAA	5-10-5	81.2	362
							405977	1649	1668	AGTCCTGCAAAACAGCTGCC	5-10-5	89.5	363
410772	1660	1679	GCTGACCATACAGTCCTGCA	5-10-5	91.2	364
							405978	1672	1691	GGCCCCGAGTGTGCTGACCA	5-10-5	95.3	365

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							399904	1675	1694	GTAGGCCCCGAGTGTGCTGA	3-14-3	92.6	54
405979	1677	1696	GTGTAGGCCCCGAGTGTGCT	5-10-5	85.5	366
							405980	1679	1698	CCGTGTAGGCCCCGAGTGTG	5-10-5	86.5	367
405981	1681	1700	ATCCGTGTAGGCCCCGAGTG	5-10-5	77.8	368
							410741	1683	1702	CCATCCGTGTAGGCCCCGAG	5-10-5	78.4	369
405982	1685	1704	GGCCATCCGTGTAGGCCCCG	5-10-5	86.7	370
							405983	1687	1706	GTGGCCATCCGTGTAGGCCC	5-10-5	73.1	371
405984	1735	1754	CTGGAGCAGCTCAGCAGCTC	5-10-5	83.4	372
							405985	1737	1756	AACTGGAGCAGCTCAGCAGC	5-10-5	50.7	373
405986	1742	1761	GGAGAAACTGGAGCAGCTCA	5-10-5	75.6	374
							405987	1744	1763	CTGGAGAAACTGGAGCAGCT	5-10-5	88.0	375
399905	1812	1831	CGTTGTGGGCCCGGCAGACC	3-14-3	91.2	57
							395183	1812	1831	CGTTGTGGGCCCGGCAGACC	5-10-5	93.1	57
410541	1849	1868	CACCTGGCAATGGCGTAGAC	5-10-5	46.1	376
							410605	1849	1868	CACCTGGCAATGGCGTAGAC	3-14-3	67.4	376
410683	1849	1868	CACCTGGCAATGGCGTAGAC	2-13-5	71.8	376
							410606	1850	1869	GCACCTGGCAATGGCGTAGA	3-14-3	74.3	377
410542	1850	1869	GCACCTGGCAATGGCGTAGA	5-10-5	75.5	377
							410684	1850	1869	GCACCTGGCAATGGCGTAGA	2-13-5	78.7	377
410543	1851	1870	AGCACCTGGCAATGGCGTAG	5-10-5	76.4	378
							410685	1851	1870	AGCACCTGGCAATGGCGTAG	2-13-5	76.9	378
410607	1851	1870	AGCACCTGGCAATGGCGTAG	3-14-3	77.1	378
							410544	1852	1871	CAGCACCTGGCAATGGCGTA	5-10-5	62.7	379
410608	1852	1871	CAGCACCTGGCAATGGCGTA	3-14-3	69.6	379
							410686	1852	1871	CAGCACCTGGCAATGGCGTA	2-13-5	81.0	379
410545	1853	1872	GCAGCACCTGGCAATGGCGT	5-10-5	75.5	380
							410687	1853	1872	GCAGCACCTGGCAATGGCGT	2-13-5	79.2	380
410609	1853	1872	GCAGCACCTGGCAATGGCGT	3-14-3	83.2	380
							410610	1854	1873	GGCAGCACCTGGCAATGGCG	3-14-3	67.5	381
410688	1854	1873	GGCAGCACCTGGCAATGGCG	2-13-5	89.3	381
							405988	1854	1873	GGCAGCACCTGGCAATGGCG	5-10-5	95.9	381
410546	1855	1874	AGGCAGCACCTGGCAATGGC	5-10-5	74.8	382
							410689	1855	1874	AGGCAGCACCTGGCAATGGC	2-13-5	83.9	382
410611	1855	1874	AGGCAGCACCTGGCAATGGC	3-14-3	88.2	382
							410612	1856	1875	CAGGCAGCACCTGGCAATGG	3-14-3	72.8	383
410690	1856	1875	CAGGCAGCACCTGGCAATGG	2-13-5	74.8	383
							405989	1856	1875	CAGGCAGCACCTGGCAATGG	5-10-5	88.1	383
410547	1857	1876	GCAGGCAGCACCTGGCAATG	5-10-5	63.0	384
							410691	1857	1876	GCAGGCAGCACCTGGCAATG	2-13-5	70.2	384
410613	1857	1876	GCAGGCAGCACCTGGCAATG	3-14-3	76.7	384
							395184	1858	1877	AGCAGGCAGCACCTGGCAAT	5-10-5	68.5	58
410692	1858	1877	AGCAGGCAGCACCTGGCAAT	2-13-5	69.1	58
							399906	1858	1877	AGCAGGCAGCACCTGGCAAT	3-14-3	94.2	58
410614	1859	1878	TAGCAGGCAGCACCTGGCAA	3-14-3	36.6	385
							410548	1859	1878	TAGCAGGCAGCACCTGGCAA	5-10-5	75.0	385
410693	1859	1878	TAGCAGGCAGCACCTGGCAA	2-13-5	82.0	385
							405990	1860	1879	GTAGCAGGCAGCACCTGGCA	5-10-5	96.8	386
410773	1905	1924	TGGCCTCAGCTGGTGGAGCT	5-10-5	61.3	387
							410549	1915	1934	GTCCCCATGCTGGCCTCAGC	5-10-5	63.0	388
410615	1915	1934	GTCCCCATGCTGGCCTCAGC	3-14-3	72.5	388
							410694	1915	1934	GTCCCCATGCTGGCCTCAGC	2-13-5	74.8	388
410550	1916	1935	GGTCCCCATGCTGGCCTCAG	5-10-5	69.4	389
							410616	1916	1935	GGTCCCCATGCTGGCCTCAG	3-14-3	80.7	389

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410695	1916	1935	GGTCCCCATGCTGGCCTCAG	2-13-5	85.5	389
410551	1917	1936	GGGTCCCCATGCTGGCCTCA	5-10-5	68.7	390
							410696	1917	1936	GGGTCCCCATGCTGGCCTCA	2-13-5	86.3	390
410617	1917	1936	GGGTCCCCATGCTGGCCTCA	3-14-3	86.5	390
							410552	1918	1937	CGGGTCCCCATGCTGGCCTC	5-10-5	77.9	391
410618	1918	1937	CGGGTCCCCATGCTGGCCTC	3-14-3	86.7	391
							410697	1918	1937	CGGGTCCCCATGCTGGCCTC	2-13-5	87.0	391
410553	1919	1938	ACGGGTCCCCATGCTGGCCT	5-10-5	72.8	392
							410619	1919	1938	ACGGGTCCCCATGCTGGCCT	3-14-3	84.1	392
410698	1919	1938	ACGGGTCCCCATGCTGGCCT	2-13-5	87.0	392
							410699	1920	1939	CACGGGTCCCCATGCTGGCC	2-13-5	79.5	59
395185	1920	1939	CACGGGTCCCCATGCTGGCC	5-10-5	92.7	59
							399907	1920	1939	CACGGGTCCCCATGCTGGCC	3-14-3	93.7	59
410620	1921	1940	ACACGGGTCCCCATGCTGGC	3-14-3	74.4	393
							410554	1921	1940	ACACGGGTCCCCATGCTGGC	5-10-5	79.7	393
410700	1921	1940	ACACGGGTCCCCATGCTGGC	2-13-5	84.4	393
							410621	1922	1941	GACACGGGTCCCCATGCTGG	3-14-3	76.0	394
410701	1922	1941	GACACGGGTCCCCATGCTGG	2-13-5	83.4	394
							405991	1922	1941	GACACGGGTCCCCATGCTGG	5-10-5	91.9	394
410555	1923	1942	GGACACGGGTCCCCATGCTG	5-10-5	77.0	395
							410622	1923	1942	GGACACGGGTCCCCATGCTG	3-14-3	79.8	395
410702	1923	1942	GGACACGGGTCCCCATGCTG	2-13-5	85.0	395
							410703	1924	1943	TGGACACGGGTCCCCATGCT	2-13-5	70.4	396
410623	1924	1943	TGGACACGGGTCCCCATGCT	3-14-3	78.9	396
							405992	1924	1943	TGGACACGGGTCCCCATGCT	5-10-5	89.3	396
410704	1925	1944	GTGGACACGGGTCCCCATGC	2-13-5	78.6	397
							410556	1925	1944	GTGGACACGGGTCCCCATGC	5-10-5	81.4	397
410624	1925	1944	GTGGACACGGGTCCCCATGC	3-14-3	82.8	397
							410625	1926	1945	AGTGGACACGGGTCCCCATG	3-14-3	64.4	398
410705	1926	1945	AGTGGACACGGGTCCCCATG	2-13-5	74.7	398
							405993	1926	1945	AGTGGACACGGGTCCCCATG	5-10-5	85.5	398
410706	1927	1946	CAGTGGACACGGGTCCCCAT	2-13-5	70.8	399
							410557	1927	1946	CAGTGGACACGGGTCCCCAT	5-10-5	74.2	399
410626	1927	1946	CAGTGGACACGGGTCCCCAT	3-14-3	76.8	399
							410627	1928	1947	GCAGTGGACACGGGTCCCCA	3-14-3	71.4	400
410707	1928	1947	GCAGTGGACACGGGTCCCCA	2-13-5	72.8	400
							405994	1928	1947	GCAGTGGACACGGGTCCCCA	5-10-5	95.2	400
410708	1929	1948	GGCAGTGGACACGGGTCCCC	2-13-5	79.0	401
							410628	1929	1948	GGCAGTGGACACGGGTCCCC	3-14-3	88.1	401
410558	1929	1948	GGCAGTGGACACGGGTCCCC	5-10-5	88.9	401
							410629	1930	1949	TGGCAGTGGACACGGGTCCC	3-14-3	66.5	402
410709	1930	1949	TGGCAGTGGACACGGGTCCC	2-13-5	66.9	402
							405995	1930	1949	TGGCAGTGGACACGGGTCCC	5-10-5	92.4	402
410630	1931	1950	GTGGCAGTGGACACGGGTCC	3-14-3	54.1	403
							410710	1931	1950	GTGGCAGTGGACACGGGTCC	2-13-5	61.4	403
410559	1931	1950	GTGGCAGTGGACACGGGTCC	5-10-5	77.5	403
							410711	1932	1951	GGTGGCAGTGGACACGGGTC	2-13-5	NA	404
410631	1932	1951	GGTGGCAGTGGACACGGGTC	3-14-3	NA	404
							410560	1932	1951	GGTGGCAGTGGACACGGGTC	5-10-5	42.5	404
410712	1933	1952	TGGTGGCAGTGGACACGGGT	2-13-5	NA	405
							410632	1933	1952	TGGTGGCAGTGGACACGGGT	3-14-3	NA	405
410561	1933	1952	TGGTGGCAGTGGACACGGGT	5-10-5	NA	405
							410774	1936	1955	TGTTGGTGGCAGTGGACACG	5-10-5	47.8	406

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410775	1962	1981	AGCTGCAGCCTGTGAGGACG	5-10-5	36.3	407
410776	1990	2009	GTGCCAAGGTCCTCCACCTC	5-10-5	77.3	408
							410777	2010	2029	TCAGCACAGGCGGCTTGTGG	5-10-5	40.0	409
410778	2040	2059	CCACGCACTGGTTGGGCTGA	5-10-5	52.7	410
							399908	2100	2119	CTTTGCATTCCAGACCTGGG	3-14-3	74.9	60
410713	2100	2119	CTTTGCATTCCAGACCTGGG	2-13-5	84.9	60
							395186	2100	2119	CTTTGCATTCCAGACCTGGG	5-10-5	93.7	60
410714	2101	2120	ACTTTGCATTCCAGACCTGG	2-13-5	82.4	411
							410633	2101	2120	ACTTTGCATTCCAGACCTGG	3-14-3	83.8	411
410562	2101	2120	ACTTTGCATTCCAGACCTGG	5-10-5	87.3	411
							410715	2102	2121	GACTTTGCATTCCAGACCTG	2-13-5	80.5	412
410634	2102	2121	GACTTTGCATTCCAGACCTG	3-14-3	81.8	412
							405996	2102	2121	GACTTTGCATTCCAGACCTG	5-10-5	91.0	412
410563	2103	2122	TGACTTTGCATTCCAGACCT	5-10-5	75.4	413
							410635	2103	2122	TGACTTTGCATTCCAGACCT	3-14-3	75.9	413
410716	2103	2122	TGACTTTGCATTCCAGACCT	2-13-5	88.3	413
							410636	2104	2123	TTGACTTTGCATTCCAGACC	3-14-3	61.3	414
410564	2104	2123	TTGACTTTGCATTCCAGACC	5-10-5	71.3	414
							410717	2104	2123	TTGACTTTGCATTCCAGACC	2-13-5	76.7	414
410718	2105	2124	CTTGACTTTGCATTCCAGAC	2-13-5	55.8	61
							399973	2105	2124	CTTGACTTTGCATTCCAGAC	3-14-3	82.1	61
399817	2105	2124	CTTGACTTTGCATTCCAGAC	5-10-5	93.6	61
							405997	2107	2126	TCCTTGACTTTGCATTCCAG	5-10-5	95.6	415
410779	2120	2139	CGGGATTCCATGCTCCTTGA	5-10-5	79.7	416
							410780	2150	2169	GCAGGCCACGGTCACCTGCT	5-10-5	60.9	417
410781	2187	2206	GGAGGGCACTGCAGCCAGTC	5-10-5	66.0	418
							410719	2305	2324	CAGATGGCAACGGCTGTCAC	2-13-5	61.0	419
410637	2305	2324	CAGATGGCAACGGCTGTCAC	3-14-3	66.0	419
							410565	2305	2324	CAGATGGCAACGGCTGTCAC	5-10-5	71.6	419
410638	2306	2325	GCAGATGGCAACGGCTGTCA	3-14-3	71.9	420
							410720	2306	2325	GCAGATGGCAACGGCTGTCA	2-13-5	75.1	420
410566	2306	2325	GCAGATGGCAACGGCTGTCA	5-10-5	77.7	420
							410639	2307	2326	AGCAGATGGCAACGGCTGTC	3-14-3	67.7	421
410721	2307	2326	AGCAGATGGCAACGGCTGTC	2-13-5	68.8	421
							410567	2307	2326	AGCAGATGGCAACGGCTGTC	5-10-5	72.1	421
410568	2308	2327	CAGCAGATGGCAACGGCTGT	5-10-5	54.2	422
							410640	2308	2327	CAGCAGATGGCAACGGCTGT	3-14-3	57.7	422
410722	2308	2327	CAGCAGATGGCAACGGCTGT	2-13-5	59.2	422
							410569	2309	2328	GCAGCAGATGGCAACGGCTG	5-10-5	57.7	423
410641	2309	2328	GCAGCAGATGGCAACGGCTG	3-14-3	66.1	423
							410723	2309	2328	GCAGCAGATGGCAACGGCTG	2-13-5	81.1	423
399909	2310	2329	GGCAGCAGATGGCAACGGCT	3-14-3	69.9	62
							410724	2310	2329	GGCAGCAGATGGCAACGGCT	2-13-5	87.4	62
395187	2310	2329	GGCAGCAGATGGCAACGGCT	5-10-5	92.7	62
							410642	2311	2330	CGGCAGCAGATGGCAACGGC	3-14-3	70.4	424
410725	2311	2330	CGGCAGCAGATGGCAACGGC	2-13-5	75.6	424
							410570	2311	2330	CGGCAGCAGATGGCAACGGC	5-10-5	78.3	424
410571	2312	2331	CCGGCAGCAGATGGCAACGG	5-10-5	52.8	425
							410643	2312	2331	CCGGCAGCAGATGGCAACGG	3-14-3	59.8	425
410726	2312	2331	CCGGCAGCAGATGGCAACGG	2-13-5	69.8	425
							410644	2313	2332	TCCGGCAGCAGATGGCAACG	3-14-3	59.0	426
410727	2313	2332	TCCGGCAGCAGATGGCAACG	2-13-5	68.3	426
							405998	2313	2332	TCCGGCAGCAGATGGCAACG	5-10-5	75.6	426

ISIS number	5 ' target site for SEQ ID NO:1	3 ' target site for SEQ ID NO:1	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410572	2314	2333	CTCCGGCAGCAGATGGCAAC	5-10-5	40.9	427
410728	2314	2333	CTCCGGCAGCAGATGGCAAC	2-13-5	56.4	427
							410645	2314	2333	CTCCGGCAGCAGATGGCAAC	3-14-3	70.2	427
410729	2315	2334	GCTCCGGCAGCAGATGGCAA	2-13-5	67.7	428
							410573	2315	2334	GCTCCGGCAGCAGATGGCAA	5-10-5	71.8	428
410646	2315	2334	GCTCCGGCAGCAGATGGCAA	3-14-3	72.8	428
							410782	2325	2344	CCAGGTGCCGGCTCCGGCAG	5-10-5	43.2	429
410783	2335	2354	GAGGCCTGCGCCAGGTGCCG	5-10-5	63.7	430
							399819	2509	2528	CCCACTCAAGGGCCAGGCCA	5-10-5	93.4	65
399912	2597	2616	ATGCCCCACAGTGAGGGAGG	3-14-3	84.3	66
							405893	2828	2847	ATGAGGGCCATCAGCACCTT	5-10-5	93.9	431
405894	2829	2848	GATGAGGGCCATCAGCACCT	5-10-5	93.9	432
							405895	2830	2849	AGATGAGGGCCATCAGCACC	5-10-5	91.8	433
405896	2831	2850	GAGATGAGGGCCATCAGCAC	5-10-5	88.5	434
							395194	2832	2851	GGAGATGAGGGCCATCAGCA	5-10-5	90.0	69
399916	2832	2851	GGAGATGAGGGCCATCAGCA	3-14-3	94.5	69
							405897	2833	2852	TGGAGATGAGGGCCATCAGC	5-10-5	85.1	435
405898	2834	2853	CTGGAGATGAGGGCCATCAG	5-10-5	86.9	436
							405899	2835	2854	GCTGGAGATGAGGGCCATCA	5-10-5	91.5	437
405900	2836	2855	AGCTGGAGATGAGGGCCATC	5-10-5	83.7	438
							405901	2902	2921	GCTAGATGCCATCCAGAAAG	5-10-5	88.4	439
405902	2903	2922	GGCTAGATGCCATCCAGAAA	5-10-5	89.3	440
							405903	2904	2923	TGGCTAGATGCCATCCAGAA	5-10-5	92.6	441
405904	2905	2924	CTGGCTAGATGCCATCCAGA	5-10-5	90.4	442
							399821	2906	2925	TCTGGCTAGATGCCATCCAG	5-10-5	91.7	71
405905	2907	2926	CTCTGGCTAGATGCCATCCA	5-10-5	90.7	443
							405906	2908	2927	CCTCTGGCTAGATGCCATCC	5-10-5	93.3	444
405907	2909	2928	GCCTCTGGCTAGATGCCATC	5-10-5	90.2	445
							405908	2910	2929	AGCCTCTGGCTAGATGCCAT	5-10-5	83.3	446
399978	2988	3007	AGCCTGGCATAGAGCAGAGT	3-14-3	96.4	73

To be lower than antisense oligonucleotide " NA " mark of 30% to the inhibition that the PCSK9mRNA level represents.

Have following ISIS number antisense oligonucleotide and represented inhibition PCSK9mRNA level at least 80%:

395152,395153,395155,395158,395163,395165,395166,395168,395173,395181,395183,395185,395186,395187,395194,399798,399801,399804,399806,399817,399819,399821,399877,399879,399887,399888,399891,399895,399900,399904,399905,399906,399907,399912,399916,399954,399960,399962,399967,399968,399969,399973,399978,405861,405862,405863,405864,405865,405866,405869,405870,405871,405872,405873,405874,405875,405876,405877,405878,405879,405880,405881,405882,405883,405884,405889,405890,405891,405893,405894,405895,405896,405897,405898,405899,405900,405901,405902,405903,405904,405905,405906,405907,405908,405909,405910,405911,405913,405914,405915,405916,405920,405921,405922,405923,405924,405925,405926,405927,405928,405929,405930,405931,405932,405934,405935,405936,405940,405941,405943,405944,405949,405952,405953,405954,405955,405956,405958,405959,405960,405961,405973,405974,405976,405977,405978,405979,405980,405982,405984,405987,405988,405989,405990,405991,405992,405993,405994,405995,405996,405997,406002,406003,406005,406008,406009,406014,406016,406020,406023,406026,406028,406029,406030,406031,406032,406033,406035,406036,406038,406039,406040,406041,406042,406043,406044,406045,410530,410556,410558,410562,410578,410583,410589,410590,410591,410592,410593,410595,410609,410611,410616,410617,410618,410619,410624,410628,410633,410634,410647,410648,410650,410652,410658,410664,410666,410667,410668,410671,410677,410686,410688,410689,410693,410695,410696,410697,410698,410700,410701,410702,410713,410714,410715,410716,410723,410724,410730,410751,410754,410757,410759,410760,410769 and 410772.

The target area section of these antisense oligonucleotide targets is active target area sections.The target area of these antisense oligonucleotide targets is active target areas.

ISIS number

395152,395155,395158,395165,395166,395168,395173,395181,395183,395185,395186,395187,395194,399801,399817,399819,399821,399877,399879,399887,399888,399891,399900,399904,399905,399906,399907,399916,399954,399962,399969,399978,405861,405862,405864,405869,405871,405872,405873,405874,405875,405876,405878,405879,405880,405881,405882,405883,405884,405890,405891,405893,405894,405895,405896,405897,405898,405899,405901,405902,405903,405904,405905,405906,405907,405910,405911,405913,405914,405915,405916,405920,405921,405922,405923,405924,405925,405926,405927,405928,405929,405930,405931,405932,405934,405935,405936,405941,405952,405953,405954,405955,405956,405959,405960,405961,405974,405977,405978,405979,405980,405982,405987,405988,405989,405990,405991,405992,405993,405994,405995,405996,405997,406008,406009,406014,406016,406023,406028,406029,406030,406031,406032,406033,406035,406038,406039,406040,406041,406042,406043,406044,406045,410558,410562,410583,410591,410592,410593,410611,410617,410618,410628,410647,410650,410668,410677,410688,410695,410696,410697,410698,410702,410716,410724,410730,410757,410760 and 410772

Represented inhibition separately to PCSK9mRNA level at least 85%.

ISIS number

395152,395155,395158,395165,395166,395168,395173,395183,395185,395186,395187,395194,399801,399817,399819,399821,399877,399879,399887,399888,399891,399900,399904,399905,399906,399907,399916,399954,399969,399978,405861,405862,405864,405873,405874,405875,405876,405878,405879,405880,405881,405882,405883,405884,405891,405893,405894,405895,405899,405903,405904,405905,405906,405907,405910,405913,405914,405916,405923,405924,405925,405926,405927,405928,405930,405932,405934,405936,405941,405953,405955,405956,405959,405960,405978,405988,405990,405991,405994,405995,405996,405997,406008,406009,406014,406023,406028,406029,406030,406033,406035,406039,406040,406041,406042,406043,406044,410592,410647,410668,410760 and 410772

Represented inhibition separately to PCSK9mRNA level at least 90%.

ISIS number 395165,395166,399801,399978,405881,405891,405959,405978,405988,405990,405994,405997,406008,406030,406040,406041,406044 and 410760 inhibition that represented separately PCSK9mRNA level at least 95%.

Table 17: the Antisense Suppression of target SEQ ID NO:2 in people's cell (HepB3) to PCSK9

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410742	2433	2452	GCCTGGAGCTGACGGTGCCC	5-10-5	75.1	159
405999	2437	2456	GACCGCCTGGAGCTGACGGT	5-10-5	70.3	160
							395151	2439	2458	AGGACCGCCTGGAGCTGACG	5-10-5	57.3	6
405861	2545	2564	AAGGCTAGCACCAGCTCCTC	5-10-5	90.5	162
							405862	2546	2565	CAAGGCTAGCACCAGCTCCT	5-10-5	92.3	163
405863	2547	2566	GCAAGGCTAGCACCAGCTCC	5-10-5	82.6	164
							405864	2548	2567	CGCAAGGCTAGCACCAGCTC	5-10-5	91.8	165
395152	2549	2568	ACGCAAGGCTAGCACCAGCT	5-10-5	93.3	7
							405865	2550	2569	AACGCAAGGCTAGCACCAGC	5-10-5	84.6	166
405866	2551	2570	GAACGCAAGGCTAGCACCAG	5-10-5	81.8	167
							405867	2552	2571	GGAACGCAAGGCTAGCACCA	5-10-5	74.0	168
405868	2553	2572	CGGAACGCAAGGCTAGCACC	5-10-5	76.8	169
							399793	2556	2575	CCTCGGAACGCAAGGCTAGC	5-10-5	77.9	8
410743	2560	2579	TCCTCCTCGGAACGCAAGGC	5-10-5	76.7	170
							410744	2585	2604	GTGCTCGGGTGCTTCGGCCA	5-10-5	76.9	171
410745	2605	2624	TGGAAGGTGGCTGTGGTTCC	5-10-5	41.7	172
							395153	2619	2638	CCTTGGCGCAGCGGTGGAAG	5-10-5	81.1	9
410746	6444	6463	CGTAGGTGCCAGGCAACCTC	5-10-5	44.8	176
							410747	6482	6501	TGACTGCGAGAGGTGGGTCT	5-10-5	NA	177
406003	6492	6511	CAGTGCGCTCTGACTGCGAG	5-10-5	84.2	178
							406004	6494	6513	GGCAGTGCGCTCTGACTGCG	5-10-5	56.4	179
406005	6496	6515	CGGGCAGTGCGCTCTGACTG	5-10-5	83.4	180
							406006	6499	6518	CGGCGGGCAGTGCGCTCTGA	5-10-5	71.0	181
410748	6528	6547	ATCCCCGGCGGGCAGCCTGG	5-10-5	56.0	182
							406007	6532	6551	AGGTATCCCCGGCGGGCAGC	5-10-5	76.3	183
410574	6534	6553	TGAGGTATCCCCGGCGGGCA	3-14-3	69.1	184
							410529	6534	6553	TGAGGTATCCCCGGCGGGCA	5-10-5	77.4	184
410647	6534	6553	TGAGGTATCCCCGGCGGGCA	2-13-5	90.7	184
							410575	6535	6554	GTGAGGTATCCCCGGCGGGC	3-14-3	71.5	185

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410648	6535	6554	GTGAGGTATCCCCGGCGGGC	2-13-5	82.8	185
410530	6535	6554	GTGAGGTATCCCCGGCGGGC	5-10-5	83.2	185
							410649	6536	6555	GGTGAGGTATCCCCGGCGGG	2-13-5	53.5	186
410576	6536	6555	GGTGAGGTATCCCCGGCGGG	3-14-3	56.2	186
							410531	6536	6555	GGTGAGGTATCCCCGGCGGG	5-10-5	63.6	186
410650	6537	6556	TGGTGAGGTATCCCCGGCGG	2-13-5	86.1	11
							399877	6537	6556	TGGTGAGGTATCCCCGGCGG	3-14-3	92.6	11
395155	6537	6556	TGGTGAGGTATCCCCGGCGG	5-10-5	92.7	11
							410577	6538	6557	TTGGTGAGGTATCCCCGGCG	3-14-3	62.4	187
410532	6538	6557	TTGGTGAGGTATCCCCGGCG	5-10-5	63.5	187
							410651	6538	6557	TTGGTGAGGTATCCCCGGCG	2-13-5	75.5	187
410652	6539	6558	CTTGGTGAGGTATCCCCGGC	2-13-5	81.2	188
							410578	6539	6558	CTTGGTGAGGTATCCCCGGC	3-14-3	83.3	188
406008	6539	6558	CTTGGTGAGGTATCCCCGGC	5-10-5	95.2	188
							410653	6540	6559	TCTTGGTGAGGTATCCCCGG	2-13-5	68.9	189
410579	6540	6559	TCTTGGTGAGGTATCCCCGG	3-14-3	74.0	189
							410533	6540	6559	TCTTGGTGAGGTATCCCCGG	5-10-5	79.0	189
410580	6541	6560	ATCTTGGTGAGGTATCCCCG	3-14-3	62.3	190
							410654	6541	6560	ATCTTGGTGAGGTATCCCCG	2-13-5	65.2	190
406009	6541	6560	ATCTTGGTGAGGTATCCCCG	5-10-5	90.7	190
							410534	6542	6561	GATCTTGGTGAGGTATCCCC	5-10-5	59.8	191
410581	6542	6561	GATCTTGGTGAGGTATCCCC	3-14-3	72.9	191
							410655	6542	6561	GATCTTGGTGAGGTATCCCC	2-13-5	77.4	191
399794	6543	6562	GGATCTTGGTGAGGTATCCC	5-10-5	56.5	12
							410656	6543	6562	GGATCTTGGTGAGGTATCCC	2-13-5	68.0	12
399950	6543	6562	GGATCTTGGTGAGGTATCCC	3-14-3	74.4	12
							410535	6544	6563	AGGATCTTGGTGAGGTATCC	5-10-5	65.7	192
410582	6544	6563	AGGATCTTGGTGAGGTATCC	3-14-3	69.5	192
							410657	6544	6563	AGGATCTTGGTGAGGTATCC	2-13-5	73.1	192
406010	6546	6565	GCAGGATCTTGGTGAGGTAT	5-10-5	56-9	193
							406011	6548	6567	ATGCAGGATCTTGGTGAGGT	5-10-5	70.7	194
406012	6550	6569	ACATGCAGGATCTTGGTGAG	5-10-5	69.1	195
							406013	6554	6573	GAAGACATGCAGGATCTTGG	5-10-5	77.4	196
395156	6557	6576	ATGGAAGACATGCAGGATCT	5-10-5	76.7	14
							410749	6565	6584	AGAAGGCCATGGAAGACATG	5-10-5	59.4	197
410750	6575	6594	GAAGCCAGGAAGAAGGCCAT	5-10-5	57.5	198
							399879	6583	6602	TTCACCAGGAAGCCAGGAAG	3-14-3	91.9	15
406014	6585	6604	TCTTCACCAGGAAGCCAGGA	5-10-5	94.0	199
							406015	6590	6609	ACTCATCTTCACCAGGAAGC	5-10-5	78.8	200
406016	6592	6611	CCACTCATCTTCACCAGGAA	5-10-5	87.2	201
							410730	6594	6613	CGCCACTCATCTTCACCAGG	5-10-5	85.4	202
406017	6596	6615	GTCGCCACTCATCTTCACCA	5-10-5	76.3	203
							406018	6598	6617	AGGTCGCCACTCATCTTCAC	5-10-5	63.2	204
406019	6600	6619	GCAGGTCGCCACTCATCTTC	5-10-5	68.1	205
							406020	6602	6621	CAGCAGGTCGCCACTCATCT	5-10-5	83.7	206
410731	6604	6623	TCCAGCAGGTCGCCACTCAT	5-10-5	72.9	207
							395158	9130	9149	CCTCGATGTAGTCGACATGG	5-10-5	93.9	17
410752	9149	9168	GCAAAGACAGAGGAGTCCTC	5-10-5	76.3	209
							406021	9207	9226	TTCATCCGCCCGGTACCGTG	5-10-5	79.6	210
406022	9209	9228	TATTCATCCGCCCGGTACCG	5-10-5	78.7	211
							406023	9212	9231	TGGTATTCATCCGCCCGGTA	5-10-5	92.5	212
406024	9214	9233	GCTGGTATTCATCCGCCCGG	5-10-5	69.7	213
							410732	9216	9235	GGGCTGGTATTCATCCGCCC	5-10-5	30.4	214

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							399935	14601	14620	AGGACCCAAGTCATCCTGCT	3-14-3	81.1	96
399936	14631	14650	GGCCATCAGCTGGCAATGCT	3-14-3	89.0	124
							410753	14877	14896	ATACACCTCCACCAGGCTGC	5-10-5	72.8	315
406025	14888	14907	GTGTCTAGGAGATACACCTC	5-10-5	74.2	216
							406026	14893	14912	TGCTGGTGTCTAGGAGATAC	5-10-5	80.5	217
405869	14918	14937	TCGATTTCCCGGTGGTCACT	5-10-5	87.6	218
							405870	14919	14938	CTCGATTTCCCGGTGGTCAC	5-10-5	83.3	219
405871	14920	14939	CCTCGATTTCCCGGTGGTCA	5-10-5	87.0	220
							405872	14921	14940	CCCTCGATTTCCCGGTGGTC	5-10-5	88.2	221
399798	14922	14941	GCCCTCGATTTCCCGGTGGT	5-10-5	84.3	22
							399954	14922	14941	GCCCTCGATTTCCCGGTGGT	3-14-3	90.3	22
405873	14923	14942	TGCCCTCGATTTCCCGGTGG	5-10-5	90.0	222
							405874	14924	14943	CTGCCCTCGATTTCCCGGTG	5-10-5	91.4	223
405875	14925	14944	CCTGCCCTCGATTTCCCGGT	5-10-5	93.5	224
							405876	14926	14945	CCCTGCCCTCGATTTCCCGG	5-10-5	90.1	225
406027	14930	14949	ATGACCCTGCCCTCGATTTC	5-10-5	73.9	226
							406028	14932	14951	CCATGACCCTGCCCTCGATT	5-10-5	92.3	227
406029	14934	14953	GACCATGACCCTGCCCTCGA	5-10-5	91.4	228
							406030	14938	14957	CGGTGACCATGACCCTGCCC	5-10-5	95.6	229
406031	14940	14959	GTCGGTGACCATGACCCTGC	5-10-5	89.6	230
							410733	14942	14961	AAGTCGGTGACCATGACCCT	5-10-5	65.7	231
406032	14944	14963	CGAAGTCGGTGACCATGACC	5-10-5	88.5	232
							410754	14954	.14973	GGCACATTCTCGAAGTCGGT	5-10-5	80.1	233
395163	14979	14998	GTGGAAGCGGGTCCCGTCCT	5-10-5	83.9	25
							410756	15254	15273	GGTGGGTGCCATGACTGTCA	5-10-5	67.1	235
406033	15261	15280	CCTGCCAGGTGGGTGCCATG	5-10-5	91.2	237
							406034	15266	15285	CCACCCCTGCCAGGTGGGTG	5-10-5	59.3	238
406035	15271	15290	GCTGACCACCCCTGCCAGGT	5-10-5	91.7	239
							410757	15279	15298	TCCCGGCCGCTGACCACCCC	5-10-5	88.9	240
406036	15283	15302	GGCATCCCGGCCGCTGACCA	5-10-5	84.0	241
							406037	15286	15305	GCCGGCATCCCGGCCGCTGA	5-10-5	55.9	242
410536	15291	15310	GCCACGCCGGCATCCCGGCC	5-10-5	63.7	243
							410658	15291	15310	GCCACGCCGGCATCCCGGCC	2-13-5	82.0	243
410583	15291	15310	GCCACGCCGGCATCCCGGCC	3-14-3	87.3	243
							410537	15292	15311	GGCCACGCCGGCATCCCGGC	5-10-5	58.5	244
410659	15292	15311	GGCCACGCCGGCATCCCGGC	2-13-5	73.7	244
							410584	15292	15311	GGCCACGCCGGCATCCCGGC	3-14-3	79.5	244
410660	15293	15312	TGGCCACGCCGGCATCCCGG	2-13-5	63.0	245
							410585	15293	15312	TGGCCACGCCGGCATCCCGG	3-14-3	73.2	245
406038	15293	15312	TGGCCACGCCGGCATCCCGG	5-10-5	86.3	245
							410661	15294	15313	TTGGCCACGCCGGCATCCCG	2-13-5	53.3	246
410586	15294	15313	TTGGCCACGCCGGCATCCCG	3-14-3	60.3	246
							405877	15294	15313	TTGGCCACGCCGGCATCCCG	5-10-5	83.2	246
410587	15295	15314	CTTGGCCACGCCGGCATCCC	3-14-3	63.2	247
							410662	15295	15314	CTTGGCCACGCCGGCATCCC	2-13-5	67.3	247
405878	15295	15314	CTTGGCCACGCCGGCATCCC	5-10-5	91.4	247
							410588	15296	15315	CCTTGGCCACGCCGGCATCC	3-14-3	65.3	248
410663	15296	15315	CCTTGGCCACGCCGGCATCC	2-13-5	67.9	248
							405879	15296	15315	CCTTGGCCACGCCGGCATCC	5-10-5	94.1	248
410589	15297	15316	CCCTTGGCCACGCCGGCATC	3-14-3	80.1	249
							410664	15297	15316	CCCTTGGCCACGCCGGCATC	2-13-5	81.9	249
405880	15297	15316	CCCTTGGCCACGCCGGCATC	5-10-5	93.5	249
							410665	15298	15317	ACCCTTGGCCACGCCGGCAT	2-13-5	78.7	28

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							399887	15298	15317	ACCCTTGGCCACGCCGGCAT	3-14-3	91.9	28
395165	15298	15317	ACCCTTGGCCACGCCGGCAT	5-10-5	96.7	28
							410590	15299	15318	CACCCTTGGCCACGCCGGCA	3-14-3	82.2	250
410666	15299	15318	CACCCTTGGCCACGCCGGCA	2-13-5	82.7	250
							405881	15299	15318	CACCCTTGGCCACGCCGGCA	5-10-5	98.3	250
410667	15300	15319	GCACCCTTGGCCACGCCGGC	2-13-5	84.7	251
							410591	15300	15319	GCACCCTTGGCCACGCCGGC	3-14-3	86.3	251
405882	15300	15319	GCACCCTTGGCCACGCCGGC	5-10-5	91.6	251
							410668	15301	15320	GGCACCCTTGGCCACGCCGG	2-13-5	91.4	252
405883	15301	15320	GGCACCCTTGGCCACGCCGG	5-10-5	92.5	252
							410592	15301	15320	GGCACCCTTGGCCACGCCGG	3-14-3	93.4	252
410669	15302	15321	TGGCACCCTTGGCCACGCCG	2-13-5	69.0	253
							410593	15302	15321	TGGCACCCTTGGCCACGCCG	3-14-3	88.8	253
405884	15302	15321	TGGCACCCTTGGCCACGCCG	5-10-5	90.8	253
							410670	15303	15322	CTGGCACCCTTGGCCACGCC	2-13-5	74.9	254
410594	15303	15322	CTGGCACCCTTGGCCACGCC	3-14-3	75.2	254
							410538	15303	15322	CTGGCACCCTTGGCCACGCC	5-10-5	78.2	254
410539	15304	15323	GCTGGCACCCTTGGCCACGC	5-10-5	61.9	255
							410595	15304	15323	GCTGGCACCCTTGGCCACGC	3-14-3	83.1	255
410671	15304	15323	GCTGGCACCCTTGGCCACGC	2-13-5	83.3	255
							410758	15309	15328	CGCATGCTGGCACCCTTGGC	5-10-5	73.6	256
406039	15330	15349	CAGTTGAGCACGCGCAGGCT	5-10-5	91.2	257
							406040	15332	15351	GGCAGTTGAGCACGCGCAGG	5-10-5	96.5	258
399888	15334	15353	TTGGCAGTTGAGCACGCGCA	3-14-3	90.9	29
							395166	15334	15353	TTGGCAGTTGAGCACGCGCA	5-10-5	96.2	29
406041	15336	15355	CCTTGGCAGTTGAGCACGCG	5-10-5	96.6	259
							399801	15339	15358	TTCCCTTGGCAGTTGAGCAC	5-10-5	95.6	30
406042	15341	15360	CCTTCCCTTGGCAGTTGAGC	5-10-5	92.0	260
							406043	15345	15364	GTGCCCTTCCCTTGGCAGTT	5-10-5	91.9	261
406044	15347	15366	CCGTGCCCTTCCCTTGGCAG	5-10-5	95.4	262
							410759	15358	15377	GGTGCCGCTAACCGTGCCCT	5-10-5	83.7	263
406045	18591	18610	TGGCTTTTCCGAATAAACTC	5-10-5	88.4	266
							395168	18593	18612	GCTGGCTTTTCCGAATAAAC	5-10-5	91.9	32
405909	18595	18614	CAGCTGGCTTTTCCGAATAA	5-10-5	80.3	267
							405910	18597	18616	ACCAGCTGGCTTTTCCGAAT	5-10-5	90.9	268
405911	18599	18618	GGACCAGCTGGCTTTTCCGA	5-10-5	88.0	269
							405912	18603	18622	GGCTGGACCAGCTGGCTTTT	5-10-5	78.2	270
410761	18614	18633	GTGGCCCCACAGGCTGGACC	5-10-5	53.7	271
							410762	18627	18646	AGCAGCACCACCAGTGGCCC	5-10-5	57.6	272
410763	18649	18668	GCTGTACCCACCCGCCAGGG	5-10-5	68.8	273
							410764	18695	18714	CGACCCCAGCCCTCGCCAGG	5-10-5	66.3	274
399891	18705	18724	GTGACCAGCACGACCCCAGC	3-14-3	91.1	33
							405913	18707	18726	CGGTGACCAGCACGACCCCA	5-10-5	93.8	275
405914	18709	18728	AGCGGTGACCAGCACGACCC	5-10-5	90.4	276
							405915	18711	18730	GCAGCGGTGACCAGCACGAC	5-10-5	86.8	277
405916	18713	18732	CGGCAGCGGTGACCAGCACG	5-10-5	91.3	278
							410734	18714	18733	CCGGCAGCGGTGACCAGCAC	5-10-5	65.8	279
405917	18717	18736	TTGCCGGCAGCGGTGACCAG	5-10-5	62.0	280
							405918	18719	18738	AGTTGCCGGCAGCGGTGACC	5-10-5	33.5	281
405919	18721	18740	GAAGTTGCCGGCAGCGGTGA	5-10-5	68.2	282
							405920	18723	18742	CGGAAGTTGCCGGCAGCGGT	5-10-5	86.2	283
405921	18725	18744	CCCGGAAGTTGCCGGCAGCG	5-10-5	85.5	284
							405922	18727	18746	GTCCCGGAAGTTGCCGGCAG	5-10-5	86.0	285

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405923	19931	19950	GGCATTGGTGGCCCCAACTG	5-10-5	94.3	288
410767	19941	19960	GCTGGTCTTGGGCATTGGTG	5-10-5	65.1	289
							405924	19954	19973	CCCAGGGTCACCGGCTGGTC	5-10-5	93.1	290
410735	19956	19975	TCCCCAGGGTCACCGGCTGG	5-10-5	78.1	291
							405925	19958	19977	AGTCCCCAGGGTCACCGGCT	5-10-5	93.5	292
405926	19960	19979	AAAGTCCCCAGGGTCACCGG	5-10-5	94.6	293
							405927	19964	19983	CCCCAAAGTCCCCAGGGTCA	5-10-5	94.5	294
405928	19969	19988	TTGGTCCCCAAAGTCCCCAG	5-10-5	90.0	295
							405929	19973	19992	AAAGTTGGTCCCCAAAGTCC	5-10-5	85.5	296
399895	19976	19995	GCCAAAGTTGGTCCCCAAAG	3-14-3	84.6	36
							395173	19976	19995	GCCAAAGTTGGTCCCCAAAG	5-10-5	94.8	36
405930	19978	19997	CGGCCAAAGTTGGTCCCCAA	5-10-5	92.9	297
							405931	19980	19999	AGCGGCCAAAGTTGGTCCCC	5-10-5	88.8	298
405932	19982	20001	ACAGCGGCCAAAGTTGGTCC	5-10-5	90.6	299
							405933	19984	20003	ACACAGCGGCCAAAGTTGGT	5-10-5	NA	300
405934	19986	20005	CCACACAGCGGCCAAAGTTG	5-10-5	92.7	301
							405935	19990	20009	AGGTCCACACAGCGGCCAAA	5-10-5	86.0	302
410736	19992	20011	AGAGGTCCACACAGCGGCCA	5-10-5	73.8	303
							405936	19994	20013	AAAGAGGTCCACACAGCGGC	5-10-5	93.9	304
410768	20016	20035	CAATGATGTCCTCCCCTGGG	5-10-5	79.7	305
							405937	20023	20042	GAGGCACCAATGATGTCCTC	5-10-5	77.7	306
405938	20027	20046	GCTGGAGGCACCAATGATGT	5-10-5	75.5	307
							405939	20029	20048	TCGCTGGAGGCACCAATGAT	5-10-5	70.6	308
405940	20031	20050	AGTCGCTGGAGGCACCAATG	5-10-5	84.4	309
							405941	20033	20052	GCAGTCGCTGGAGGCACCAA	5-10-5	90.1	310
399804	20036	20055	GCTGCAGTCGCTGGAGGCAC	5-10-5	80.8	40
							399960	20036	20055	GCTGCAGTCGCTGGAGGCAC	3-14-3	82.4	40
405942	20038	20057	GTGCTGCAGTCGCTGGAGGC	5-10-5	69.8	311
							405943	20040	20059	AGGTGCTGCAGTCGCTGGAG	5-10-5	83.6	312
410737	20042	20061	GCAGGTGCTGCAGTCGCTGG	5-10-5	49.8	313
							405944	20043	20062	AGCAGGTGCTGCAGTCGCTG	5-10-5	80.7	314
405945	20045	20064	AAAGCAGGTGCTGCAGTCGC	5-10-5	41.1	315
							405946	20049	20068	ACACAAAGCAGGTGCTGCAG	5-10-5	70.4	316
405947	20051	20070	TGACACAAAGCAGGTGCTGC	5-10-5	72.5	317
							410769	20061	20080	TCCCACTCTGTGACACAAAG	5-10-5	84.9	318
405949	20629	20648	CAGCATCATGGCTGCAATGC	5-10-5	84.9	320
							405950	20631	20650	GACAGCATCATGGCTGCAAT	5-10-5	76.9	321
405951	20633	20652	CAGACAGCATCATGGCTGCA	5-10-5	75.4	322
							405952	20637	20656	TCGGCAGACAGCATCATGGC	5-10-5	85.1	323
410738	20639	20658	GCTCGGCAGACAGCATCATG	5-10-5	68.4	324
							405953	20641	20660	CGGCTCGGCAGACAGCATCA	5-10-5	93.6	325
405954	20643	20662	TCCGGCTCGGCAGACAGCAT	5-10-5	87.5	326
							410770	20657	20676	CGGCCAGGGTGAGCTCCGGC	5-10-5	68.5	327
405955	20670	20689	CTCTGCCTCAACTCGGCCAG	5-10-5	94.2	328
							405956	20672	20691	GTCTCTGCCTCAACTCGGCC	5-10-5	94.3	329
405958	20676	20695	ATCAGTCTCTGCCTCAACTC	5-10-5	80.3	331
							405959	20678	20697	GGATCAGTCTCTGCCTCAAC	5-10-5	95.4	332
405960	20680	20699	GTGGATCAGTCTCTGCCTCA	5-10-5	90.1	333
							405961	20682	20701	AAGTGGATCAGTCTCTGCCT	5-10-5	88.8	334
405962	20685	20704	GAGAAGTGGATCAGTCTCTG	5-10-5	56.1	335
							410739	20687	20706	CAGAGAAGTGGATCAGTCTC	5-10-5	NA	33.6
405963	20689	20708	GGCAGAGAAGTGGATCAGTC	5-10-5	59.7	337
							405964	20693	20712	CTTTGGCAGAGAAGTGGATC	5-10-5	45.3	338

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405965	20698	20717	GACATCTTTGGCAGAGAAGT	5-10-5	55.9	339
405966	20700	20719	ATGACATCTTTGGCAGAGAA	5-10-5	51.3	340
							405967	20704	20723	ATTGATGACATCTTTGGCAG	5-10-5	64.4	341
405968	20706	20725	TCATTGATGACATCTTTGGC	5-10-5	74.6	342
							399967	20709	20728	GCCTCATTGATGACATCTTT	3-14-3	80.1	48
405969	20711	20730	AGGCCTCATTGATGACATCT	5-10-5	63.0	343
							405970	20713	20732	CCAGGCCTCATTGATGACAT	5-10-5	66.8	344
410740	20715	20734	AACCAGGCCTCATTGATGAC	5-10-5	46.8	345
							405885	20717	20736	GGAACCAGGCCTCATTGATG	5-10-5	73.4	346
410596	20719	20738	AGGGAACCAGGCCTCATTGA	3-14-3	NA	348
							410672	20719	20738	AGGGAACCAGGCCTCATTGA	2-13-5	NA	348
405887	20719	20738	AGGGAACCAGGCCTCATTGA	5-10-5	NA	348
							410597	20720	20739	CAGGGAACCAGGCCTCATTG	3-14-3	NA	349
405888	20720	20739	CAGGGAACCAGGCCTCATTG	5-10-5	NA	349
							410673	20720	20739	CAGGGAACCAGGCCTCATTG	2-13-5	NA	349
410674	20721	20740	TCAGGGAACCAGGCCTCATT	2-13-5	60.7	49
							399812	20721	20740	TCAGGGAACCAGGCCTCATT	5-10-5	68.7	49
399968	20721	20740	TCAGGGAACCAGGCCTCATT	3-14-3	84.5	49
							410598	20722	20741	CTCAGGGAACCAGGCCTCAT	3-14-3	74.5	350
410675	20722	20741	CTCAGGGAACCAGGCCTCAT	2-13-5	76.9	350
							405889	20722	20741	CTCAGGGAACCAGGCCTCAT	5-10-5	80.2	350
410599	20723	20742	CCTCAGGGAACCAGGCCTCA	3-14-3	70.6	351
							410676	20723	20742	CCTCAGGGAACCAGGCCTCA	2-13-5	77.8	351
405890	20723	20742	CCTCAGGGAACCAGGCCTCA	5-10-5	87.7	351
							410600	20724	20743	TCCTCAGGGAACCAGGCCTC	3-14-3	76.5	352
410677	20724	20743	TCCTCAGGGAACCAGGCCTC	2-13-5	88.4	352
							405891	20724	20743	TCCTCAGGGAACCAGGCCTC	5-10-5	96.1	352
405892	20725	20744	GTCCTCAGGGAACCAGGCCT	5-10-5	71.4	353
							410601	20725	20744	GTCCTCAGGGAACCAGGCCT	3-14-3	72.7	353
410678	20725	20744	GTCCTCAGGGAACCAGGCCT	2-13-5	75.0	353
							395178	20726	20745	GGTCCTCAGGGAACCAGGCC	5-10-5	76.7	50
410679	20726	20745	GGTCCTCAGGGAACCAGGCC	2-13-5	77.6	50
							399900	20726	20745	GGTCCTCAGGGAACCAGGCC	3-14-3	92.0	50
408653	20727	20746	TGGTCCTCAGGGAACCAGGC	5-10-5	42.5	354
							410602	20727	20746	TGGTCCTCAGGGAACCAGGC	3-14-3	66.5	354
410680	20727	20746	TGGTCCTCAGGGAACCAGGC	2-13-5	71.6	354
							410603	20728	20747	CTGGTCCTCAGGGAACCAGG	3-14-3	40.8	355
410681	20728	20747	CTGGTCCTCAGGGAACCAGG	2-13-5	44.4	355
							405971	20728	20747	CTGGTCCTCAGGGAACCAGG	5-10-5	65.5	355
410540	20729	20748	GCTGGTCCTCAGGGAACCAG	5-10-5	50.9	356
							410682	20729	20748	GCTGGTCCTCAGGGAACCAG	2-13-5	54.1	356
410604	20729	20748	GCTGGTCCTCAGGGAACCAG	3-14-3	62.5	356
							405972	20730	20749	CGCTGGTCCTCAGGGAACCA	5-10-5	77.6	357
405973	20735	20754	GTACCCGCTGGTCCTCAGGG	5-10-5	83.8	358
							405974	20737	20756	CAGTACCCGCTGGTCCTCAG	5-10-5	89.0	359
399813	20740	20759	GGTCAGTACCCGCTGGTCCT	5-10-5	72.4	51
							399969	20740	20759	GGTCAGTACCCGCTGGTCCT	3-14-3	93.4	51
410771	20785	20804	ACCTGCCCCATGGGTGCTGG	5-10-5	NA	360
							405975	21088	21107	CAAAACAGCTGCCAACCTGC	5-10-5	77.4	361
405976	21093	21112	TCCTGCAAAACAGCTGCCAA	5-10-5	81.2	362
							405977	21095	21114	AGTCCTGCAAAACAGCTGCC	5-10-5	89.5	363
410772	21106	21125	GCTGACCATACAGTCCTGCA	5-10-5	91.2	264
							405978	21118	21137	GGCCCCGAGTGTGCTGACCA	5-10-5	95.3	365

ISIS number	5 ' target site for SEQ ID NO:2	3 target sites for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							399904	21121	21140	GTAGGCCCCGAGTGTGCTGA	3-14-3	92.6	54
405979	21123	21142	GTGTAGGCCCCGAGTGTGCT	5-10-5	85.5	366
							405980	21125	21144	CCGTGTAGGCCCCGAGTGTG	5-10-5	86.5	367
405981	21127	21146	ATCCGTGTAGGCCCCGAGTG	5-10-5	77.8	368
							410741	21129	21148	CCATCCGTGTAGGCCCCGAG	5-10-5	78.4	369
405982	21131	21150	GGCCATCCGTGTAGGCCCCG	5-10-5	86.7	370
							405983	21133	21152	GTGGCCATCCGTGTAGGCCC	5-10-5	73.1	371
405984	21181	21200	CTGGAGCAGCTCAGCAGCTC	5-10-5	83.4	372
							405985	21183	21202	AACTGGAGCAGCTCAGCAGC	5-10-5	50.7	373
405986	21188	21207	GGAGAAACTGGAGCAGCTCA	5-10-5	75.6	374
							405987	21190	21209	CTGGAGAAACTGGAGCAGCT	5-10-5	88.0	375
399868	21696	21715	GGCACTGCCCTTCCACCAAA	5-10-5	85.8	123
							399905	22096	22115	CGTTGTGGGCCCGGCAGACC	3-14-3	91.2	57
395183	22096	22115	CGTTGTGGGCCCGGCAGACC	5-10-5	93.1	57
							410541	22133	22152	CACCTGGCAATGGCGTAGAC	5-10-5	46.1	376
410605	22133	22152	CACCTGGCAATGGCGTAGAC	3-14-3	67.4	376
							410683	22133	22152	CACCTGGCAATGGCGTAGAC	2-13-5	71.8	376
410606	22134	22153	GCACCTGGCAATGGCGTAGA	3-14-3	74.3	377
							410542	22134	22153	GCACCTGGCAATGGCGTAGA	5-10-5	75.5	377
410684	22134	22153	GCACCTGGCAATGGCGTAGA	2-13-5	78.7	377
							410543	22135	22154	AGCACCTGGCAATGGCGTAG	5-10-5	76.4	378
410685	22135	22154	AGCACCTGGCAATGGCGTAG	2-13-5	76.9	378
							410607	22135	22154	AGCACCTGGCAATGGCGTAG	3-14-3	77.1	378
410544	22136	22155	CAGCACCTGGCAATGGCGTA	5-10-5	62.7	379
							410608	22136	22155	CAGCACCTGGCAATGGCGTA	3-14-3	69.6	379
410686	22136	22155	CAGCACCTGGCAATGGCGTA	2-13-5	81.0	379
							410545	22137	22156	GCAGCACCTGGCAATGGCGT	5-10-5	75.5	380
410687	22137	22156	GCAGCACCTGGCAATGGCGT	2-13-5	79.2	380
							410609	22137	22156	GCAGCACCTGGCAATGGCGT	3-14-3	83.2	380
410610	22138	22157	GGCAGCACCTGGCAATGGCG	3-14-3	67.5	381
							410688	22138	22157	GGCAGCACCTGGCAATGGCG	2-13-5	89.3	381
405988	22138	22157	GGCAGCACCTGGCAATGGCG	5-10-5	95.9	381
							410546	22139	22158	AGGCAGCACCTGGCAATGGC	5-10-5	74.8	382
410689	22139	22158	AGGCAGCACCTGGCAATGGC	2-13-5	83.9	382
							410611	22139	22158	AGGCAGCACCTGGCAATGGC	3-14-3	88.2	382
410612	22140	22159	CAGGCAGCACCTGGCAATGG	3-14-3	72.8	383
							410690	22140	22159	CAGGCAGCACCTGGCAATGG	2-13-5	74.8	383
405989	22140	22159	CAGGCAGCACCTGGCAATGG	5-10-5	88.1	383
							410547	22141	22160	GCAGGCAGCACCTGGCAATG	5-10-5	63.0	384
410691	22141	22160	GCAGGCAGCACCTGGCAATG	2-13-5	70.2	384
							410613	22141	22160	GCAGGCAGCACCTGGCAATG	3-14-3	76.7	384
395184	22142	22161	AGCAGGCAGCACCTGGCAAT	5-10-5	68.5	58
							410692	22142	22161	AGCAGGCAGCACCTGGCAAT	2-13-5	69.1	58
399906	22142	22161	AGCAGGCAGCACCTGGCAAT	3-14-3	94.2	58
							410614	22143	22162	TAGCAGGCAGCACCTGGCAA	3-14-3	36.6	385
410548	22143	22162	TAGCAGGCAGCACCTGGCAA	5-10-5	75.0	385
							410693	22143	22162	TAGCAGGCAGCACCTGGCAA	2-13-5	82.0	385
405990	22144	22163	GTAGCAGGCAGCACCTGGCA	5-10-5	96.8	386
							410773	22189	22208	TGGCCTCAGCTGGTGGAGCT	5-10-5	61.3	387
410549	22199	22218	GTCCCCATGCTGGCCTCAGC	5-10-5	63.0	388
							410615	22199	22218	GTCCCCATGCTGGCCTCAGC	3-14-3	72.5	388
410694	22199	22218	GTCCCCATGCTGGCCTCAGC	2-13-5	74.8	388
							410550	22200	22219	GGTCCCCATGCTGGCCTCAG	5-10-5	69.4	389

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410616	22200	22219	GGTCCCCATGCTGGCCTCAG	3-14-3	80.7	389
410695	22200	22219	GGTCCCCATGCTGGCCTCAG	2-13-5	85.5	389
							410551	22201	22220	GGGTCCCCATGCTGGCCTCA	5-10-5	68.7	390
410696	22201	22220	GGGTCCCCATGCTGGCCTCA	2-13-5	86.3	390
							410617	22201	22220	GGGTCCCCATGCTGGCCTCA	3-14-3	86.5	390
410552	22202	22221	CGGGTCCCCATGCTGGCCTC	5-10-5	77.9	391
							410618	22202	22221	CGGGTCCCCATGCTGGCCTC	3-14-3	86.7	391
410697	22202	22221	CGGGTCCCCATGCTGGCCTC	2-13-5	87.0	391
							410553	22203	22222	ACGGGTCCCCATGCTGGCCT	5-10-5	72.8	392
410619	22203	22222	ACGGGTCCCCATGCTGGCCT	3-14-3	84.1	392
							410698	22203	22222	ACGGGTCCCCATGCTGGCCT	2-13-5	87.0	392
410699	22204	22223	CACGGGTCCCCATGCTGGCC	2-13-5	79.5	59
							395185	22204	22223	CACGGGTCCCCATGCTGGCC	5-10-5	92.7	59
399907	22204	22223	CACGGGTCCCCATGCTGGCC	3-14-3	93.7	59
							410620	22205	22224	ACACGGGTCCCCATGCTGGC	3-14-3	74.4	393
410554	22205	22224	ACACGGGTCCCCATGCTGGC	5-10-5	79.7	393
							410700	22205	22224	ACACGGGTCCCCATGCTGGC	2-13-5	84.4	393
410621	22206	22225	GACACGGGTCCCCATGCTGG	3-14-3	76.0	394
							410701	22206	22225	GACACGGGTCCCCATGCTGG	2-13-5	83.4	394
405991	22206	22225	GACACGGGTCCCCATGCTGG	5-10-5	91.9	394
							410555	22207	22226	GGACACGGGTCCCCATGCTG	5-10-5	77.0	395
410622	22207	22226	GGACACGGGTCCCCATGCTG	3-14-3	79.8	395
							410702	22207	22226	GGACACGGGTCCCCATGCTG	2-13-5	85.0	395
410703	22208	22227	TGGACACGGGTCCCCATGCT	2-13-5	70.4	396
							410623	22208	22227	TGGACACGGGTCCCCATGCT	3-14-3	78.9	396
405992	22208	22227	TGGACACGGGTCCCCATGCT	5-10-5	89.3	396
							410704	22209	22228	GTGGACACGGGTCCCCATGC	2-13-5	78.6	397
410556	22209	22228	GTGGACACGGGTCCCCATGC	5-10-5	81.4	397
							410624	22209	22228	GTGGACACGGGTCCCCATGC	3-14-3	82.8	397
410625	22210	22229	AGTGGACACGGGTCCCCATG	3-14-3	64.4	398
							410705	22210	22229	AGTGGACACGGGTCCCCATG	2-13-5	74.7	398
405993	22210	22229	AGTGGACACGGGTCCCCATG	5-10-5	85.5	398
							410706	22211	22230	CAGTGGACACGGGTCCCCAT	2-13-5	70.8	399
410557	22211	22230	CAGTGGACACGGGTCCCCAT	5-10-5	74.2	399
							410626	22211	22230	CAGTGGACACGGGTCCCCAT	3-14-3	76.8	399
410627	22212	22231	GCAGTGGACACGGGTCCCCA	3-14-3	71.4	400
							410707	22212	22231	GCAGTGGACACGGGTCCCCA	2-13-5	72.8	400
405994	22212	22231	GCAGTGGACACGGGTCCCCA	5-10-5	95.2	400
							410708	22213	22232	GGCAGTGGACACGGGTCCCC	2-13-5	79.0	401
410628	22213	22232	GGCAGTGGACACGGGTCCCC	3-14-3	88.1	401
							410558	22213	22232	GGCAGTGGACACGGGTCCCC	5-10-5	88.9	401
410629	22214	22233	TGGCAGTGGACACGGGTCCC	3-14-3	66.5	402
							410709	22214	22233	TGGCAGTGGACACGGGTCCC	2-13-5	66.9	402
405995	22214	22233	TGGCAGTGGACACGGGTCCC	5-10-5	92.4	402
							410630	22215	22234	GTGGCAGTGGACACGGGTCC	3-14-3	54.1	403
410710	22215	22234	GTGGCAGTGGACACGGGTCC	2-13-5	61.4	403
							410559	22215	22234	GTGGCAGTGGACACGGGTCC	5-10-5	77.5	403
410711	22216	22235	GGTGGCAGTGGACACGGGTC	2-13-5	NA	404
							410631	22216	22235	GGTGGCAGTGGACACGGGTC	3-14-3	NA	404
410560	22216	22235	GGTGGCAGTGGACACGGGTC	5-10-5	42.5	404
							410712	22217	22236	TGGTGGCAGTGGACACGGGT	2-13-5	NA	405
410632	22217	22236	TGGTGGCAGTGGACACGGGT	3-14-3	NA	405
							410561	22217	22236	TGGTGGCAGTGGACACGGGT	5-10-5	NA	405

ISIS number	5 ' target site for SEQ ID NO:2	3 target sites for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410774	22220	22239	TGTTGGTGGCAGTGGACACG	5-10-5	47.8	406
410776	23985	24004	GTGCCAAGGTCCTCCACCTC	5-10-5	77.3	408
							410777	24005	24024	TCAGCACAGGCGGCTTGTGG	5-10-5	40.0	409
410778	24035	24054	CCACGCACTGGTTGGGCTGA	5-10-5	52.7	410
							399908	24095	24114	CTTTGCATTCCAGACCTGGG	3-14-3	74.9	60
410713	24095	24114	CTTTGCATTCCAGACCTGGG	2-13-5	84.9	60
							395186	24095	24114	CTTTGCATTCCAGACCTGGG	5-10-5	93.7	60
410714	24096	24115	ACTTTGCATTCCAGACCTGG	2-13-5	82.4	411
							410633	24096	24115	ACTTTGCATTCCAGACCTGG	3-14-3	83.8	411
410562	24096	24115	ACTTTGCATTCCAGACCTGG	5-10-5	87.3	411
							410715	24097	24116	GACTTTGCATTCCAGACCTG	2-13-5	80.5	412
410634	24097	24116	GACTTTGCATTCCAGACCTG	3-14-3	81.8	412
							405996	24097	24116	GACTTTGCATTCCAGACCTG	5-10-5	91.0	412
410563	24098	24117	TGACTTTGCATTCCAGACCT	5-10-5	75.4	413
							410635	24098	24117	TGACTTTGCATTCCAGACCT	3-14-3	75.9	413
410716	24098	24117	TGACTTTGCATTCCAGACCT	2-13-5	88.3	413
							410636	24099	24118	TTGACTTTGCATTCCAGACC	3-14-3	61.3	414
410564	24099	24118	TTGACTTTGCATTCCAGACC	5-10-5	71.3	414
							410717	24099	24118	TTGACTTTGCATTCCAGACC	2-13-5	76.7	414
410718	24100	24119	CTTGACTTTGCATTCCAGAC	2-13-5	55.8	61
							399973	24100	24119	CTTGACTTTGCATTCCAGAC	3-14-3	82.1	61
399817	24100	24119	CTTGACTTTGCATTCCAGAC	5-10-5	93.6	61
							405997	24102	24121	TCCTTGACTTTGCATTCCAG	5-10-5	95.6	415
410779	24115	24134	CGGGATTCCATGCTCCTTGA	5-10-5	79.7	416
							410781	25994	26013	GGAGGGCACTGCAGCCAGTC	5-10-5	66.0	418
410719	26112	26131	CAGATGGCAACGGCTGTCAC	2-13-5	61.0	419
							410637	26112	26131	CAGATGGCAACGGCTGTCAC	3-14-3	66.0	419
410565	26112	26131	CAGATGGCAACGGCTGTCAC	5-10-5	71.6	419
							410638	26113	26132	GCAGATGGCAACGGCTGTCA	3-14-3	71.9	420
410720	26113	26132	GCAGATGGCAACGGCTGTCA	2-13-5	75.1	420
							410566	26113	26132	GCAGATGGCAACGGCTGTCA	5-10-5	77.7	420
410639	26114	26133	AGCAGATGGCAACGGCTGTC	3-14-3	67.7	421
							410721	26114	26133	AGCAGATGGCAACGGCTGTC	2-13-5	68.8	421
410567	26114	26133	AGCAGATGGCAACGGCTGTC	5-10-5	72.1	421
							410568	26115	26134	CAGCAGATGGCAACGGCTGT	5-10-5	54.2	422
410640	26115	26134	CAGCAGATGGCAACGGCTGT	3-14-3	57.7	422
							410722	26115	26134	CAGCAGATGGCAACGGCTGT	2-13-5	59.2	422
410569	26116	26135	GCAGCAGATGGCAACGGCTG	5-10-5	57.7	423
							410641	26116	26135	GCAGCAGATGGCAACGGCTG	3-14-3	66.1	423
410723	26116	26135	GCAGCAGATGGCAACGGCTG	2-13-5	81.1	423
							399909	26117	26136	GGCAGCAGATGGCAACGGCT	3-14-3	69.9	62
410724	26117	26136	GGCAGCAGATGGCAACGGCT	2-13-5	87.4	62
							395187	26117	26136	GGCAGCAGATGGCAACGGCT	5-10-5	92.7	62
410642	26118	26137	CGGCAGCAGATGGCAACGGC	3-14-3	70.4	424
							410725	26118	26137	CGGCAGCAGATGGCAACGGC	2-13-5	75.6	424
410570	26118	26137	CGGCAGCAGATGGCAACGGC	5-10-5	78.3	424
							410571	26119	26138	CCGGCAGCAGATGGCAACGG	5-10-5	52.8	425
410643	26119	26138	CCGGCAGCAGATGGCAACGG	3-14-3	59.8	425
							410726	26119	26138	CCGGCAGCAGATGGCAACGG	2-13-5	69.8	425
410644	26120	26139	TCCGGCAGCAGATGGCAACG	3-14-3	59.0	426
							410727	26120	26139	TCCGGCAGCAGATGGCAACG	2-13-5	68.3	426
405998	26120	26139	TCCGGCAGCAGATGGCAACG	5-10-5	75.6	426
							410572	26121	26140	CTCCGGCAGCAGATGGCAAC	5-10-5	40.9	427

ISIS number	5 ' target site for SEQ ID NO:2	3 ' target site for SEQ ID NO:2	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410728	26121	26140	CTCCGGCAGCAGATGGCAAC	2-13-5	56.4	427
410645	26121	26140	CTCCGGCAGCAGATGGCAAC	3-14-3	70.2	427
							410729	26122	26141	GCTCCGGCAGCAGATGGCAA	2-13-5	67.7	428
410573	26122	26141	GCTCCGGCAGCAGATGGCAA	5-10-5	71.8	428
							410646	26122	26141	GCTCCGGCAGCAGATGGCAA	3-14-3	72.8	428
410782	26132	26151	CCAGGTGCCGGCTCCGGCAG	5-10-5	43.2	429
							410783	26142	26161	GAGGCCTGCGCCAGGTGCCG	5-10-5	63.7	430
399819	26316	26335	CCCACTCAAGGGCCAGGCCA	5-10-5	93.4	65
							399912	26404	26423	ATGCCCCACAGTGAGGGAGG	3-14-3	84.3	66
405893	26635	26654	ATGAGGGCCATCAGCACCTT	5-10-5	93.9	431
							405894	26636	26655	GATGAGGGCCATCAGCACCT	5-10-5	93.9	432
405895	26637	26656	AGATGAGGGCCATCAGCACC	5-10-5	91.8	433
							405896	26638	26657	GAGATGAGGGCCATCAGCAC	5-10-5	88.5	434
395194	26639	26658	GGAGATGAGGGCCATCAGCA	5-10-5	90.0	69
							399916	26639	26658	GGAGATGAGGGCCATCAGCA	3-14-3	94.5	69
405897	26640	26659	TGGAGATGAGGGCCATCAGC	5-10-5	85.1	435
							405898	26641	26660	CTGGAGATGAGGGCCATCAG	5-10-5	86.9	436
405899	26642	26661	GCTGGAGATGAGGGCCATCA	5-10-5	91.5	437
							405900	26643	26662	AGCTGGAGATGAGGGCCATC	5-10-5	83.7	438
405901	26709	26728	GCTAGATGCCATCCAGAAAG	5-10-5	88.4	439
							405902	26710	26729	GGCTAGATGCCATCCAGAAA	5-10-5	89.3	440
405903	26711	26730	TGGCTAGATGCCATCCAGAA	5-10-5	92.6	441
							405904	26712	26731	CTGGCTAGATGCCATCCA GA	5-10-5	90.4	442
399821	26713	26732	TCTGGCTAGATGCCATCCAG	5-10-5	91.7	71
							405905	26714	26733	CTCTGGCTAGATGCCATCCA	5-10-5	90.7	443
405906	26715	26734	CCTCTGGCTAGATGCCATCC	5-10-5	93.3	444
							405907	26716	26735	GCCTCTGGCTAGATGCCATC	5-10-5	90.2	445
405908	26717	26736	AGCCTCTGGCTAGATGCCAT	5-10-5	83.3	446
							399978	26795	26814	AGCCTGGCATAGAGCAGAGT	3-14-3	96.4	73

To be lower than antisense oligonucleotide " NA " mark of 30% to the inhibition that the PCSK9mRNA level represents.

Have following ISIS number antisense oligonucleotide and represented inhibition PCSK9 mRNA level at least 80%:

395152,395153,395155,395158,395163,395165,395166,395168,395173,395183,395185,395186,395187,395194,399798,399801,399804,399817,399819,399821,399868,399877,399879,399887,399888,399891,399895,399900,399904,399905,399906,399907,399912,399916,399935,399936,399954,399960,399967,399968,399969,399973,399978,405861,405862,405863,405864,405865,405866,405869,405870,405871,405872,405873,405874,405875,405876,405877,405878,405879,405880,405881,405882,405883,405884,405889,405890,405891,405893,405894,405895,405896,405897,405898,405899,405900,405901,405902,405903,405904,405905,405906,405907,405908,405909,405910,405911,405913,405914,405915,405916,405920,405921,405922,405923,405924,405925,405926,405927,405928,405929,405930,405931,405932,405934,405935,405936,405940,405941,405943,405944,405949,405952,405953,405954,405955,405956,405958,405959,405960,405961,405973,405974,405976,405977,405978,405979,405980,405982,405984,405987,405988,405989,405990,405991,405992,405993,405994,405995,405996,405997,406003,406005,406008,406009,406014,406016,406020,406023,406026,406028,406029,406030,406031,406032,406033,406035,406036,406038,406039,406040,406041,406042,406043,406044,406045,410530,410556,410558,410562,410578,410583,410589,410590,410591,410592,410593,410595,410609,410611,410616,410617,410618,410619,410624,410628,410633,410634,410647,410648,410650,410652,410658,410664,410666,410667,410668,410671,410677,410686,410688,410689,410693,410695,410696,410697,410698,410700,410701,410702,410713,410714,410715,410716,410723,410724,410730,410754, the target area section of 410757,410759,410769 and 410772. these antisense oligonucleotide targets is active target area sections.The target area of these antisense oligonucleotide targets is active target areas.

ISIS number

395152,395155,395158,395165,395166,395168,395173,395183,395185,395186,395187,395194,399801,399817,399819,399821,399868,399877,399879,399887,399888,399891,399900,399904,399905,399906,399907,399916,399936,399954,399969,399978,405861,405862,405864,405869,405871,405872,405873,405874,405875,405876,405878,405879,405880,405881,405882,405883,405884,405890,405891,405893,405894,405895,405896,405897,405898,405899,405901,405902,405903,405904,405905,405906,405907,405910,405911,405913,405914,405915,405916,405920,405921,405922,405923,405924,405925,405926,405927,405928,405929,405930,405931,405932,405934,405935,405936,405941,405952,405953,405954,405955,405956,405959,405960,405961,405974,405977,405978,405979,405980,405982,405987,405988,405989,405990,405991,405992,405993,405994,405995,405996,405997,406008,406009,406014,406016,406023,406028,406029,406030,406031,406032,406033,406035,406038,406039,406040,406041,406042,406043,406044,406045,410558,410562,410583,410591,410592,410593,410611,410617,410618,410628,410647,410650,410668,410677,410688,410695,410696,410697,410698,410702,410716,410724,410730,410757 and 410772 have represented the inhibition to PCSK9mRNA level at least 85% separately.

ISIS number

395152,395155,395158,395165,395166,395168,395173,395183,395185,395186,395187,399801,399817,399819,399821,399877,399879,399887,399888,399891,399900,399904,399905,399906,399907,399916,399969,399978,405862,405864,405874,405875,405878,405879,405880,405881,405882,405883,405884,405891,405893,405894,405895,405899,405903,405906,405910,405913,405916,405923,405924,405925,405926,405927,405930,405934,405936,405953,405955,405956,405959,405978,405988,405990,405991,405994,405995,405996,405997,406008,406014,406023,406028,406029,406030,406033,406035,406039,406040,406041,406042,406043,406044,410592,410647,410668 and 410772 have represented the inhibition to PCSK9mRNA level at least 90% separately.

ISIS number 395165,395166,399801,399978,405881,405891,405959,405978,405988,405990,405994,405997,406008,406030,406040,406041 and 406044 inhibition that represented separately PCSK9mRNA level at least 95%.

Table 18: the Antisense Suppression of target SEQ ID NO:3 in people's cell (HepB3) to PCSK9

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							399935	1075	1094	AGGACCCAAGTCATCCTGCT	3-14-3	81.1	96
399936	1105	1124	GGCCATCAGCTGGCAATGCT	3-14-3	89.0	124
							410753	1351	1370	ATACACCTCCACCAGGCTGC	5-10-5	72.8	215
406025	1362	1381	GTGTCTAGGAGATACACCTC	5-10-5	74.2	216
							406026	1367	1386	TGCTGGTGTCTAGGAGATAC	5-10-5	80.5	217
405869	1392	1411	TCGATTTCCCGGTGGTCACT	5-10-5	87.6	218
							405870	1393	1412	CTCGATTTCCCGGTGGTCAC	5-10-5	83.3	219
405871	1394	1413	CCTCGATTTCCCGGTGGTCA	5-10-5	87.0	220
							405872	1395	1414	CCCTCGATTTCCCGGTGGTC	5-10-5	88.2	221
399798	1396	1415	GCCCTCGATTTCCCGGTGGT	5-10-5	84.3	22
							399954	1396	1415	GCCCTCGATTTCCCGGTGGT	3-14-3	90.3	22
405873	1397	1416	TGCCCTCGATTTCCCGGTGG	5-10-5	90.0	222
							405874	1398	1417	CTGCCCTCGATTTCCCGGTG	5-10-5	91.4	223
405875	1399	1418	CCTGCCCTCGATTTCCCGGT	5-10-5	93.5	224
							405876	1400	1419	CCCTGCCCTCGATTTCCCGG	5-10-5	90.1	225
406027	1404	1423	ATGACCCTGCCCTCGATTTC	5-10-5	73.9	226
							406028	1406	1425	CCATGACCCTGCCCTCGATT	5-10-5	92.3	227
406029	1408	1427	GACCATGACCCTGCCCTCGA	5-10-5	91.4	228
							406030	1412	1431	CGGTGACCATGACCCTGCCC	5-10-5	95.6	229
406031	1414	1433	GTCGGTGACCATGACCCTGC	5-10-5	89.6	230
							410733	1416	1435	AAGTCGGTGACCATGACCCT	5-10-5	65.7	231
406032	1418	1437	CGAAGTCGGTGACCATGACC	5-10-5	88.5	232
							410754	1428	1447	GGCACATTCTCGAAGTCGGT	5-10-5	80.1	233
395163	1453	1472	GTGGAAGCGGGTCCCGTCCT	5-10-5	83.9	25
							410755	1463	1482	TGGCCTGTCTGTGGAAGCGG	5-10-5	NA	234
410756	1490	1509	GGTGGGTGCCATGACTGTCA	5-10-5	67.1	235
							406033	1497	1516	CCTGCCAGGTGGGTGCCATG	5-10-5	91.2	237
406034	1502	1521	CCACCCCTGCCAGGTGGGTG	5-10-5	59.3	238
							406035	1507	1526	GCTGACCACCCCTGCCAGGT	5-10-5	91.7	239
410757	1515	1534	TCCCGGCCGCTGACCACCCC	5-10-5	88.9	240
							406036	1519	1538	GGCATCCCGGCCGCTGACCA	5-10-5	84.0	241
406037	1522	1541	GCCGGCATCCCGGCCGCTGA	5-10-5	55.9	242
							410536	1527	1546	GCCACGCCGGCATCCCGGCC	5-10-5	63.7	243
410658	1527	1546	GCCACGCCGGCATCCCGGCC	2-13-5	82.0	243

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							410583	1527	1546	GCCACGCCGGCATCCCGGCC	3-14-3	87.3	243
410537	1528	1547	GGCCACGCCGGCATCCCGGC	5-10-5	58.5	244
							410659	1528	1547	GGCCACGCCGGCATCCCGGC	2-13-5	73.7	244
410584	1528	1547	GGCCACGCCGGCATCCCGGC	3-14-3	79.5	244
							410660	1529	1548	TGGCCACGCCGGCATCCCGG	2-13-5	63.0	245
410585	1529	1548	TGGCCACGCCGGCATCCCGG	3-14-3	73.2	245
							406038	1529	1548	TGGCCACGCCGGCATCCCGG	5-10-5	86.3	245
410661	1530	1549	TTGGCCACGCCGGCATCCCG	2-13-5	53.3	246
							410586	1530	1549	TTGGCCACGCCGGCATCCCG	3-14-3	60.3	246
405877	1530	1549	TTGGCCACGCCGGCATCCCG	5-10-5	83.2	246
							410587	1531	1550	CTTGGCCACGCCGGCATCCC	3-14-3	63.2	247
410662	1531	1550	CTTGGCCACGCCGGCATCCC	2-13-5	67.3	247
							405878	1531	1550	CTTGGCCACGCCGGCATCCC	5-10-5	91.4	247
410588	1532	1551	CCTTGGCCACGCCGGCATCC	3-14-3	65.3	248
							410663	1532	1551	CCTTGGCCACGCCGGCATCC	2-13-5	67.9	248
405879	1532	1551	CCTTGGCCACGCCGGCATCC	5-10-5	94.1	248
							410589	1533	1552	CCCTTGGCCACGCCGGCATC	3-14-3	80.1	249
410664	1533	1552	CCCTTGGCCACGCCGGCATC	2-13-5	81.9	249
							405880	1533	1552	CCCTTGGCCACGCCGGCATC	5-10-5	93.5	249
410665	1534	1553	ACCCTTGGCCACGCCGGCAT	2-13-5	78.7	28
							399887	1534	1553	ACCCTTGGCCACGCCGGCAT	3-14-3	91.9	28
395165	1534	1553	ACCCTTGGCCACGCCGGCAT	5-10-5	96.7	28
							410590	1535	1554	CACCCTTGGCCACGCCGGCA	3-14-3	82.2	250
410666	1535	1554	CACCCTTGGCCACGCCGGCA	2-13-5	82.7	250
							405881	1535	1554	CACCCTTGGCCACGCCGGCA	5-10-5	98.3	250
410667	1536	1555	GCACCCTTGGCCACGCCGGC	2-13-5	84.7	251
							410591	1536	1555	GCACCCTTGGCCACGCCGGC	3-14-3	86.3	251
405882	1536	1555	GCACCCTTGGCCACGCCGGC	5-10-5	91.6	251
							410668	1537	1556	GGCACCCTTGGCCACGCCGG	2-13-5	91.4	252
405883	1537	1556	GGCACCCTTGGCCACGCCGG	5-10-5	92.5	252
							410592	1537	1556	GGCACCCTTGGCCACGCCGG	3-14-3	93.4	252
410669	1538	1557	TGGCACCCTTGGCCACGCCG	2-13-5	69.0	253
							410593	1538	1557	TGGCACCCTTGGCCACGCCG	3-14-3	88.8	253
405884	1538	1557	TGGCACCCTTGGCCACGCCG	5-10-5	90.8	253
							410670	1539	1558	CTGGCACCCTTGGCCACGCC	2-13-5	74.9	254
410594	1539	1558	CTGGCACCCTTGGCCACGCC	3-14-3	75.2	254
							410538	1539	1558	CTGGCACCCTTGGCCACGCC	5-10-5	78.2	254
410539	1540	1559	GCTGGCACCCTTGGCCACGC	5-10-5	61.9	255
							410595	1540	1559	GCTGGCACCCTTGGCCACGC	3-14-3	83.1	255
410671	1540	1559	GCTGGCACCCTTGGCCACGC	2-13-5	83.3	255
							410758	1545	1564	CGCATGCTGGCACCCTTGGC	5-10-5	73.6	256
406039	1566	1585	CAGTTGAGCACGCGCAGGCT	5-10-5	91.2	257
							406040	1568	1587	GGCAGTTGAGCACGCGCAGG	5-10-5	96.5	258
399888	1570	1589	TTGGCAGTTGAGCACGCGCA	3-14-3	90.9	29
							395166	1570	1589	TTGGCAGTTGAGCACGCGCA	5-10-5	96.2	29
406041	1572	1591	CCTTGGCAGTTGAGCACGCG	5-10-5	96.6	259
							399801	1575	1594	TTCCCTTGGCAGTTGAGCAC	5-10-5	95.6	30
406042	1577	1596	CCTTCCCTTGGCAGTTGAGC	5-10-5	92.0	260
							406043	1581	1600	GTGCCCTTCCCTTGGCAGTT	5-10-5	91.9	261
406044	1583	1602	CCGTGCCCTTCCCTTGGCAG	5-10-5	95.4	262
							410759	1594	1613	GGTGCCGCTAACCGTGCCCT	5-10-5	83.7	263
410760	1618	1637	CCGAATAAACTCCAGGCCTA	5-10-5	96.7	265
							406045	1626	1645	TGGCTTTTCCGAATAAACTC	5-10-5	88.4	266

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							395168	1628	1647	GCTGGCTTTTCCGAATAAAC	5-10-5	91.9	32
405909	1630	1649	CAGCTGGCTTTTCCGAATAA	5-10-5	80.3	267
							405910	1632	1651	ACCAGCTGGCTTTTCCGAAT	5-10-5	90.9	268
405911	1634	1653	GGACCAGCTGGCTTTTCCGA	5-10-5	88.0	269
							405912	1638	1657	GGCTGGACCAGCTGGCTTTT	5-10-5	78.2	270
410761	1649	1668	GTGGCCCCACAGGCTGGACC	5-10-5	53.7	271
							410762	1662	1681	AGCAGCACCACCAGTGGCCC	5-10-5	57.6	272
410763	1684	1703	GCTGTACCCACCCGCCAGGG	5-10-5	68.8	273
							410764	1730	1749	CGACCCCAGCCCTCGCCAGG	5-10-5	66.3	274
399891	1740	1759	GTGACCAGCACGACCCCAGC	3-14-3	91.1	33
							405913	1742	1761	CGGTGACCAGCACGACCCCA	5-10-5	93.8	275
405914	1744	1763	AGCGGTGACCAGCACGACCC	5-10-5	90.4	276
							405915	1746	1765	GCAGCGGTGACCAGCACGAC	5-10-5	86.8	277
405916	1748	1767	CGGCAGCGGTGACCAGCACG	5-10-5	91.3	278
							410734	1749	1768	CCGGCAGCGGTGACCAGCAC	5-10-5	65.8	249
405917	1752	1771	TTGCCGGCAGCGGTGACCAG	5-10-5	62.0	280
							405918	1754	1773	AGTTGCCGGCAGCGGTGACC	5-10-5	33.5	281
405919	1756	1775	GAAGTTGCCGGCAGCGGTGA	5-10-5	68.2	282
							405920	1758	1777	CGGAAGTTGCCGGCAGCGGT	5-10-5	86.2	283
405921	1760	1779	CCCGGAAGTTGCCGGCAGCG	5-10-5	85.5	284
							405922	1762	1781	GTCCCGGAAGTTGCCGGCAG	5-10-5	86.0	285
405937	1820	1839	GAGGCACCAATGATGTCCTC	5-10-5	77.7	306
							405938	1824	1843	GCTGGAGGCACCAATGATGT	5-10-5	75.5	307
405939	1826	1845	TCGCTGGAGGCACCAATGAT	5-10-5	70.6	308
							405940	1828	1847	AGTCGCTGGAGGCACCAATG	5-10-5	84.4	309
405941	1830	1849	GCAGTCGCTGGAGGCACCAA	5-10-5	90.1	310
							399804	1833	1852	GCTGCAGTCGCTGGAGGCAC	5-10-5	80.8	40
399960	1833	1852	GCTGCAGTCGCTGGAGGCAC	3-14-3	82.4	40
							405942	1835	1854	GTGCTGCAGTCGCTGGAGGC	5-10-5	69.8	311
405943	1837	1856	AGGTGCTGCAGTCGCTGGAG	5-10-5	83.6	312
							410737	1839	1858	GCAGGTGCTGCAGTCGCTGG	5-10-5	49.8	313
405944	1840	1859	AGCAGGTGCTGCAGTCGCTG	5-10-5	80.7	314
							405945	1842	1861	AAAGCAGGTGCTGCAGTCGC	5-10-5	41.1	315
405946	1846	1865	ACACAAAGCAGGTGCTGCAG	5-10-5	70.4	316
							405947	1848	1867	TGACACAAAGCAGGTGCTGC	5-10-5	72.5	317
410769	1858	1877	TCCCACTCTGTGACACAAAG	5-10-5	84.9	318
							405948	1900	1919	TCATGGCTGCAATGCCAGCC	5-10-5	45.9	319
399806	1903	1922	GCATCATGGCTGCAATGCCA	5-10-5	82.8	42
							399962	1903	1922	GCATCATGGCTGCAATGCCA	3-14-3	86.1	42
405949	1905	1924	CAGCATCATGGCTGCAATGC	5-10-5	84.9	320
							405950	1907	1926	GACAGCATCATGGCTGCAAT	5-10-5	76.9	321
405951	1909	1928	CAGACAGCATCATGGCTGCA	5-10-5	75.4	322
							405952	1913	1932	TCGGCAGACAGCATCATGGC	5-10-5	85.1	323
410738	1915	1934	GCTCGGCAGACAGCATCATG	5-10-5	68.4	324
							405953	1917	1936	CGGCTCGGCAGACAGCATCA	5-10-5	93.6	325
405954	1919	1938	TCCGGCTCGGCAGACAGCAT	5-10-5	87.5	326
							410770	1933	1952	CGGCCAGGGTGAGCTCCGGC	5-10-5	68.5	327
405955	1946	1965	CTCTGCCTCAACTCGGCCAG	5-10-5	94.2	328
							405956	1948	1967	GTCTCTGCCTCAACTCGGCC	5-10-5	94.3	329
405958	1952	1971	ATCAGTCTCTGCCTCAACTC	5-10-5	80.3	331
							405959	1954	1973	GGATCAGTCTCTGCCTCAAC	5-10-5	95.4	332
405960	1956	1975	GTGGATCAGTCTCTGCCTCA	5-10-5	90.1	333
							405961	1958	1977	AAGTGGATCAGTCTCTGCCT	5-10-5	88.8	334

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405962	1961	1980	GAGAAGTGGATCAGTCTCTG	5-10-5	56.1	335
410739	1963	1982	CAGAGAAGTGGATCAGTCTC	5-10-5	NA	336
							405963	1965	1984	GGCAGAGAAGTGGATCAGTC	5-10-5	59.7	337
405964	1969	1988	CTTTGGCAGAGAAGTGGATC	5-10-5	45.3	338
							405965	1974	1993	GACATCTTTGGCAGAGAAGT	5-10-5	55.9	339
405966	1976	1995	ATGACATCTTTGGCAGAGAA	5-10-5	51.3	340
							405967	1980	1999	ATTGATGACATCTTTGGCAG	5-10-5	64.4	341
405968	1982	2001	TCATTGATGACATCTTTGGC	5-10-5	74.6	342
							399967	1985	2004	GCCTCATTGATGACATCTTT	3-14-3	80.1	48
405969	1987	2006	AGGCCTCATTGATGACATCT	5-10-5	63.0	343
							405970	1989	2008	CCAGGCCTCATTGATGACAT	5-10-5	66.8	344
410740	1991	2010	AACCAGGCCTCATTGATGAC	5-10-5	46.8	345
							405885	1993	2012	GGAACCAGGCCTCATTGATG	5-10-5	73.4	346
410596	1995	2014	AGGGAACCAGGCCTCATTGA	3-14-3	NA	348
							410672	1995	2014	AGGGAACCAGGCCTCATTGA	2-13-5	NA	348
405887	1995	2014	AGGGAACCAGGCCTCATTGA	5-10-5	NA	348
							410597	1996	2015	CAGGGAACCAGGCCTCATTG	3-14-3	NA	349
405888	1996	2015	CAGGGAACCAGGCCTCATTG	5-10-5	NA	349
							410673	1996	2015	CAGGGAACCAGGCCTCATTG	2-13-5	NA	349
410674	1997	2016	TCAGGGAACCAGGCCTCATT	2-13-5	60.7	49
							399812	1997	2016	TCAGGGAACCAGGCCTCATT	5-10-5	68.7	49
399968	1997	2016	TCAGGGAACCAGGCCTCATT	3-14-3	84.5	49
							410598	1998	2017	CTCAGGGAACCAGGCCTCAT	3-14-3	74.5	350
410675	1998	2017	CTCAGGGAACCAGGCCTCAT	2-13-5	76.9	350
							405889	1998	2017	CTCAGGGAACCAGGCCTCAT	5-10-5	80.2	350
410599	1999	2018	CCTCAGGGAACCAGGCCTCA	3-14-3	70.6	351
							410676	1999	2018	CCTCAGGGAACCAGGCCTCA	2-13-5	77.8	351
405890	1999	2018	CCTCAGGGAACCAGGCCTCA	5-10-5	87.7	351
							410600	2000	2019	TCCTCAGGGAACCAGGCCTC	3-14-3	76.5	352
410677	2000	2019	TCCTCAGGGAACCAGGCCTC	2-13-5	88.4	352
							405891	2000	2019	TCCTCAGGGAACCAGGCCTC	5-10-5	96.1	352
405892	2001	2020	GTCCTCAGGGAACCAGGCCT	5-10-5	71.4	353
							410601	2001	2020	GTCCTCAGGGAACCAGGCCT	3-14-3	72.7	353
410678	2001	2020	GTCCTCAGGGAACCAGGCCT	2-13-5	75.0	353
							395178	2002	2021	GGTCCTCAGGGAACCAGGCC	5-10-5	76.7	50
410679	2002	2021	GGTCCTCAGGGAACCAGGCC	2-13-5	77.6	50
							399900	2002	2021	GGTCCTCAGGGAACCAGGCC	3-14-3	92.0	50
408653	2003	2022	TGGTCCTCAGGGAACCAGGC	5-10-5	42.5	354
							410602	2003	2022	TGGTCCTCAGGGAACCAGGC	3-14-3	66.5	354
410680	2003	2022	TGGTCCTCAGGGAACCAGGC	2-13-5	71.6	354
							410603	2004	2023	CTGGTCCTCAGGGAACCAGG	3-14-3	40.8	355
410681	2004	2023	CTGGTCCTCAGGGAACCAGG	2-13-5	44.4	355
							405971	2004	2023	CTGGTCCTCAGGGAACCAGG	5-10-5	65.5	355
410540	2005	2024	GCTGGTCCTCAGGGAACCAG	5-10-5	50.9	356
							410682	2005	2024	GCTGGTCCTCAGGGAACCAG	2-13-5	54.1	356
410604	2005	2024	GCTGGTCCTCAGGGAACCAG	3-14-3	62.5	356
							405972	2006	2025	CGCTGGTCCTCAGGGAACCA	5-10-5	77.6	357
405973	2011	2030	GTACCCGCTGGTCCTCAGGG	5-10-5	83.8	358
							405974	2013	2032	CAGTACCCGCTGGTCCTCAG	5-10-5	89.0	359
399813	2016	2035	GGTCAGTACCCGCTGGTCCT	5-10-5	72.4	51
							399969	2016	2035	GGTCAGTACCCGCTGGTCCT	3-14-3	93.4	51
410771	2061	2080	ACCTGCCCCATGGGTGCTGG	5-10-5	NA	360
							395181	2073	2092	AAACAGCTGCCAACCTGCCC	5-10-5	87.5	52

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO
							405975	2075	2094	CAAAACAGCTGCCAACCTGC	5-10-5	77.4	361
405976	2080	2099	TCCTGCAAAACAGCTGCCAA	5-10-5	81.2	362
							405977	2082	2101	AGTCCTGCAAAACAGCTGCC	5-10-5	89.5	363
399992	2095	2114	GTGCTGACCACACAGTCCTG	3-14-3	92.6	130
							405978	2105	2124	GGCCCCGAGTGTGCTGACCA	5-10-5	95.3	365
399904	2108	2127	GTAGGCCCCGAGTGTGCTGA	3-14-3	92.6	54
							405979	2110	2129	GTGTAGGCCCCGAGTGTGCT	5-10-5	85.5	366
405980	2112	2131	CCGTGTAGGCCCCGAGTGTG	5-10-5	86.5	367
							405981	2114	2133	ATCCGTGTAGGCCCCGAGTG	5-10-5	77.8	368
410741	2116	2135	CCATCCGTGTAGGCCCCGAG	5-10-5	78.4	369
							405982	2118	2137	GGCCATCCGTGTAGGCCCCG	5-10-5	86.7	370
405983	2120	2139	GTGGCCATCCGTGTAGGCCC	5-10-5	73.1	371
							405984	2168	2187	CTGGAGCAGCTCAGCAGCTC	5-10-5	83.4	372
405985	2170	2189	AACTGGAGCAGCTCAGCAGC	5-10-5	50.7	373
							405986	2175	2194	GGAGAAACTGGAGCAGCTCA	5-10-5	75.6	374
405987	2177	2196	CTGGAGAAACTGGAGCAGCT	5-10-5	88.0	375
							410776	2245	2264	GTGCCAAGGTCCTCCACCTC	5-10-5	77.3	408
410777	2265	2284	TCAGCACAGGCGGCTTGTGG	5-10-5	40.0	409
							410778	2295	2314	CCACGCACTGGTTGGGCTGA	5-10-5	52.7	410
399908	2355	2374	CTTTGCATTCCAGACCTGGG	3-14-3	74.9	60
							410713	2355	2374	CTTTGCATTCCAGACCTGGG	2-13-5	84.9	60
395186	2355	2374	CTTTGCATTCCAGACCTGGG	5-10-5	93.7	60
							410714	2356	2375	ACTTTGCATTCCAGACCTGG	2-13-5	82.4	411
410633	2356	2375	ACTTTGCATTCCAGACCTGG	3-14-3	83.8	411
							410562	2356	2375	ACTTTGCATTCCAGACCTGG	5-10-5	87.3	411
410715	2357	2376	GACTTTGCATTCCAGACCTG	2-13-5	80.5	412
							410634	2357	2376	GACTTTGCATTCCAGACCTG	3-14-3	81.8	412
405996	2357	2376	GACTTTGCATTCCAGACCTG	5-10-5	91.0	412
							410563	2358	2377	TGACTTTGCATTCCAGACCT	5-10-5	75.4	413
410635	2358	2377	TGACTTTGCATTCCAGACCT	3-14-3	75.9	413
							410716	2358	2377	TGACTTTGCATTCCAGACCT	2-13-5	88.3	413
410636	2359	2378	TTGACTTTGCATTCCAGACC	3-14-3	61.3	414
							410564	2359	2378	TTGACTTTGCATTCCAGACC	5-10-5	71.3	414
410717	2359	2378	TTGACTTTGCATTCCAGACC	2-13-5	76.7	414
							410718	2360	2379	CTTGACTTTGCATTCCAGAC	2-13-5	55.8	61
399973	2360	2379	CTTGACTTTGCATTCCAGAC	3-14-3	82.1	61
							399817	2360	2379	CTTGACTTTGCATTCCAGAC	5-10-5	93.6	61
405997	2362	2381	TCCTTGACTTTGCATTCCAG	5-10-5	95.6	415
							410779	2375	2394	CGGGATTCCATGCTCCTTGA	5-10-5	79.7	416
410780	2405	2424	GCAGGCCACGGTCACCTGCT	5-10-5	60.9	417
							410781	2442	2461	GGAGGGCACTGCAGCCAGTC	5-10-5	66.0	418
410719	2560	2579	CAGATGGCAACGGCTGTCAC	2-13-5	61.0	419
							410637	2560	2579	CAGATGGCAACGGCTGTCAC	3-14-3	66.0	419
410565	2560	2579	CAGATGGCAACGGCTGTCAC	5-10-5	71.6	419
							410638	2561	2580	GCAGATGGCAACGGCTGTCA	3-14-3	71.9	420
410720	2561	2580	GCAGATGGCAACGGCTGTCA	2-13-5	75.1	420
							410566	2561	2580	GCAGATGGCAACGGCTGTCA	5-10-5	77.7	420
410639	2562	2581	AGCAGATGGCAACGGCTGTC	3-14-3	67.7	421
							410721	2562	2581	AGCAGATGGCAACGGCTGTC	2-13-5	68.8	421
410567	2562	2581	AGCAGATGGCAACGGCTGTC	5-10-5	72.1	421
							410568	2563	2582	CAGCAGATGGCAACGGCTGT	5-10-5	54.2	422
410640	2563	2582	CAGCAGATGGCAACGGCTGT	3-14-3	57.7	422
							410722	2563	2582	CAGCAGATGGCAACGGCTGT	2-13-5	59.2	422

ISIS number	5 ' target site for SEQ ID NO:3	3 ' target site for SEQ ID NO:3	Sequence 5 '-3 '	Motif	% suppresses	SEQ ID NO：
							410569	2564	2583	GCAGCAGATGGCAACGGCTG	5-10-5	57.7	423
410641	2564	2583	GCAGCAGATGGCAACGGCTG	3-14-3	66.1	423
							410723	2564	2583	GCAGCAGATGGCAACGGCTG	2-13-5	81.1	423
399909	2565	2584	GGCAGCAGATGGCAACGGCT	3-14-3	69.9	62
							410724	2565	2584	GGCAGCAGATGGCAACGGCT	2-13-5	87.4	62
395187	2565	2584	GGCAGCAGATGGCAACGGCT	5-10-5	92.7	62
							410642	2566	2585	CGGCAGCAGATGGCAACGGC	3-14-3	70.4	424
410725	2566	2585	CGGCAGCAGATGGCAACGGC	2-13-5	75.6	424
							410570	2566	2585	CGGCAGCAGATGGCAACGGC	5-10-5	78.3	424
410571	2567	2586	CCGGCAGCAGATGGCAACGG	5-10-5	52.8	425
							410643	2567	2586	CCGGCAGCAGATGGCAACGG	3-14-3	59.8	425
410726	2567	2586	CCGGCAGCAGATGGCAACGG	2-13-5	69.8	425
							410644	2568	2587	TCCGGCAGCAGATGGCAACG	3-14-3	59.0	426
410727	2568	2587	TCCGGCAGCAGATGGCAACG	2-13-5	68.3	426
							405998	2568	2587	TCCGGCAGCAGATGGCAACG	5-10-5	75.6	426
405988	2568	2587	TCCGGCAGCAGATGGCAACG	5-10-5	84.5	426
							410572	2569	2588	CTCCGGCAGCAGATGGCAAC	5-10-5	40.9	427
410728	2569	2588	CTCCGGCAGCAGATGGCAAC	2-13-5	56.4	427
							410645	2569	2588	CTCCGGCAGCAGATGGCAAC	3-14-3	70.2	427
410729	2570	2589	GCTCCGGCAGCAGATGGCAA	2-13-5	67.7	428
							410573	2570	2589	GCTCCGGCAGCAGATGGCAA	5-10-5	71.8	428
410646	2570	2589	GCTCCGGCAGCAGATGGCAA	3-14-3	72.8	428
							410782	2580	2599	CCAGGTGCCGGCTCCGGCAG	5-10-5	43.2	429
410783	2590	2609	GAGGCCTGCGCCAGGTGCCG	5-10-5	63.7	430
							399819	2764	2783	CCCACTCAAGGGCCAGGCCA	5-10-5	93.4	65
399912	2852	2871	ATGCCCCACAGTGAGGGAGG	3-14-3	84.3	66
							405893	3083	3102	ATGAGGGCCATCAGCACCTT	5-10-5	93.9	431
405894	3084	3103	GATGAGGGCCATCAGCACCT	5-10-5	93.9	432
							405895	3085	3104	AGATGAGGGCCATCAGCACC	5-10-5	91.8	433
405896	3086	3105	GAGATGAGGGCCATCAGCAC	5-10-5	88.5	434
							395194	3087	3106	GGAGATGAGGGCCATCAGCA	5-10-5	90.0	69
399916	3087	3106	GGAGATGAGGGCCATCAGCA	3-14-3	94.5	69
							405897	3088	3107	TGGAGATGAGGGCCATCAGC	5-10-5	85.1	435
405898	3089	3108	CTGGAGATGAGGGCCATCAG	5-10-5	86.9	436
							405899	3090	3109	GCTGGAGATGAGGGCCATCA	5-10-5	91.5	437
405900	3091	3110	AGCTGGAGATGAGGGCCATC	5-10-5	83.7	438
							405901	3157	3176	GCTAGATGCCATCCAGAAAG	5-10-5	88.4	439
405902	3158	3177	GGCTAGATGCCATCCAGAAA	5-10-5	89.3	440
							405903	3159	3178	TGGCTAGATGCCATCCAGAA	5-10-5	92.6	441
405904	3160	3179	CTGGCTAGATGCCATCCAGA	5-10-5	90.4	442
							399821	3161	3180	TCTGGCTAGATGCCATCCAG	5-10-5	91.7	71
405905	3162	3181	CTCTGGCTAGATGCCATCCA	5-10-5	90.7	443
							405906	3163	3182	CCTCTGGCTAGATGCCATCC	5-10-5	93.3	444
405907	3164	3183	GCCTCTGGCTAGATGCCATC	5-10-5	90.2	445
							405908	3165	3184	AGCCTCTGGCTAGATGCCAT	5-10-5	83.3	446
399978	3243	3262	AGCCTGGCATAGAGCAGAGT	3-14-3	96.4	73

To be lower than antisense oligonucleotide " NA " mark of 30% to the inhibition that PCSK9 mRNA level represents.

Have following ISIS number antisense oligonucleotide and represented inhibition PCSK9mRNA level at least 80%:

395163,395165,395166,395168,395181,395186,395187,395194,399798,399801,399804,399806,399817,399819,399821,399887,399888,399891,399900,399904,399912,399916,399935,399936,399954,399960,399962,399967,399968,399969,399973,399978,399992,405869,405870,405871,405872,405873,405874,405875,405876,405877,405878,405879,405880,405881,405882,405883,405884,405889,405890,405891,405893,405894,405895,405896,405897,405898,405899,405900,405901,405902,405903,405904,405905,405906,405907,405908,405909,405910,405911,405913,405914,405915,405916,405920,405921,405922,405940,405941,405943,405944,405949,405952,405953,405954,405955,405956,405958,405959,405960,405961,405973,405974,405976,405977,405978,405979,405980,405982,405984,405987,405988,405996,405997,406026,406028,406029,406030,406031,406032,406033,406035,406036,406038,406039,406040,406041,406042,406043,406044,406045,410562,410583,410589,410590,410591,410592,410593,410595,410633,410634,410658,410664,410666,410667,410668,410671,410677,410713,410714,410715,410716,410723,410724, the target area section of 410754,410757,410759,410760 and 410769. these antisense oligonucleotide targets is active target area sections.The target area of these antisense oligonucleotide targets is active target areas.

ISIS number

395165,395166,395168,395181,395186,395187,395194,399801,399817,399819,399821,399887,399888,399891,399900,399904,399916,399936,399954,399962,399969,399978,399992,405869,405871,405872,405873,405874,405875,405876,405878,405879,405880,405881,405882,405883,405884,405890,405891,405893,405894,405895,405896,405897,405898,405899,405901,405902,405903,405904,405905,405906,405907,405910,405911,405913,405914,405915,405916,405920,405921,405922,405941,405952,405953,405954,405955,405956,405959,405960,405961,405974,405977,405978,405979,405980,405982,405987,405996,405997,406028,406029,406030,406031,406032,406033,406035,406038,406039,406040,406041,406042,406043,406044,406045,410562,410583,410591,410592,410593,410668,410677,410716,410724,410757 and 410760 have represented the inhibition to PCSK9mRNA level at least 85% separately.

ISIS number

395165,395166,395168,395186,395187,395194,399801,399817,399819,399821,399887,399888,399891,399900,399904,399916,399954,399969,399978,399992,405873,405874,405875,405876,405878,405879,405880,405881,405882,405883,405884,405891,405893,405894,405895,405899,405903,405904,405905,405906,405907,405910,405913,405914,405916,405941,405953,405955,405956,405959,405960,405978,405996,405997,406028,406029,406030,406033,406035,406039,406040,406041,406042,406043,406044,410592,410668 and 410760 have represented the inhibition to PCSK9mRNA level at least 90% separately.

ISIS number 395165,395166,399801,399978,405881,405891,405959,405978,405997,406030,406040,406041,406044 and 410760 inhibition that represented separately PCSK9mRNA level at least 95%.

Embodiment 4: in the HepG2 cell to the Antisense Suppression of people PCSK9: the dose response experiment

In the HepG2 cell, tested the antisense oligonucleotide of target PCSK9 with various dose.With the density bed board of cell, and handle with the antisense oligonucleotide of the nM concentration shown in table 19 and 20 with 10,000 cells in every hole.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.Used two kinds of different people PCSK9 primer probe groups to measure the mRNA level.Use the table 19 that the results are shown in of primer probe groups 2740, and the mRNA level of using primer probe groups 2823 to measure is shown in table 20.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.As cited in table 19 and 20, the PCSK9mRNA level reduces in the dose-dependently mode.

Table 19: in the HepG2 cell to the Antisense Suppression of PCSK9, primer probe groups 2740

ISIS number	200.0nM	100.0nM	50.0nM	25.0nM	12.5nM	6.25nM
							399819	93	113	84	71	26	12
395185	81	64	50	35	24	13
							399916	65	56	41	18	20	25
399907	68	66	42	26	30	25
							399954	71	63	38	22	16	15
395165	71	67	47	29	21	10
							399936	65	51	31	20	30	28
399793	61	57	44	31	39	15
							399969	57	54	40	27	25	19
395152	75	58	58	49	24	28

Table 20: in the HepG2 cell to the Antisense Suppression of PCSK9, primer probe groups 2823

ISIS number	200.0nM	100.0nM	50.0nM	25.0nM	12.5nM	6.25nM
							399819	80	264	87	85	34	15
395185	86	66	57	45	29	22
							399916	75	47	45	20	30	45
399907	67	72	47	29	31	32
							399954	59	50	35	17	22	27
395165	74	54	41	37	26	22
							399936	62	41	33	32	28	42
399793	62	51	38	36	44	27
							399969	73	40	58	28	29	35
395152	78	53	64	49	22	35

Embodiment 5: in the HepB3 cell to the Antisense Suppression of people PCSK9: the dose response experiment

In the HepB3 cell, tested the antisense oligonucleotide of target PCSK9 with various dose.With the density bed board of cell, and handle with the antisense oligonucleotide of the nM concentration shown in the table 21 with 4,500 cells in every hole.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.Used two kinds of different people PCSK9 primer probe groups to measure the mRNA level.Use the table 21 that the results are shown in of primer probe groups 2740.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.As cited in the table 21, the PCSK9mRNA level reduces in the dose-dependently mode.

Table 21: in the HepB3 cell to the Antisense Suppression of PCSK9, primer probe groups 2740

ISIS number	75.0nM	25.0nM	8.33nM	2.78nM
					399819	127.5	85.0	36.1	21.9
405891	133.7	111.4	40.2	27.2
					406008	144.6	108.3	49.9	17.7
395186	124.4	106.4	42.2	30.7
					395185	150.7	106.6	53.6	38.1
405994	141.9	101.2	49.3	30.8
					405988	148.1	117.4	47.8	25.2
406033	138.1	109.9	62.4	35.3
					395187	133.0	115.6	59.9	31.6
405995	124.1	109.2	57.8	42.9
					406023	130.0	103.5	67.1	28.0
399900	131.2	95.7	81.1	30.9
					301012	121.2	100.1	63.8	49.6
395165	113.2	86.9	41.6	13.3
					405879	124.6	88.8	44.1	13.1
405991	100.6	101.4	95.9	41.0
					405923	130.4	115.0	68.9	35.1
395152	143.8	98.6	61.3	59.0
					405881	100.7	77.4	50.2	4.5
141923	131.4	131.9	144.0	167.3

Embodiment 6: in the HeLa cell to the Antisense Suppression of people PCSK9: the dose response experiment

In the HeLa cell, tested the antisense oligonucleotide of target PCSK9 with various dose.With the density bed board of cell, and handle with the antisense oligonucleotide of the nM concentration shown in the table 22 with 5,000 cells in every hole.After about 24 hours processing phase, from cellular segregation RNA, and measured the PCSK9mRNA level by quantitative PCR in real time, as described herein.Used two kinds of different people PCSK9 primer probe groups to measure the mRNA level.Use the table 22 that the results are shown in of primer probe groups 2740.According to usefulness

Total rna content of measuring is adjusted the PCSK9mRNA level.The per-cent to PCSK9 that the result is expressed as with respect to untreatment control cell suppresses.As cited in the table 22, the PCSK9mRNA level reduces in the dose-dependently mode.

Table 22: in the HeLa cell to the Antisense Suppression of PCSK9, primer probe groups 2740

ISIS number	80.0nM	26.6667nM	8.8889nM	2.963nM
					399819	57	32	16	14
405891	57	46	17	18
					406008	45	27	11	5.3
395186	40	28	11	6.6
					395185	53	32	21	17
405994	48	34	20	13
					405988	44	32	12	7.3
406033	61	42	25	12
					395187	42	35	12	6.6
405995	54	39	21	15
					406023	76	46	25	6.2
399900	85	48	23	6.4
					301012	121	109	76	65
395165	61	30	10	2
					405879	64	32	9.7	1
405991	64	35	24	10
					405923	71	45	22	5
395152	73	34	13	3.1
					405881	58	33	19	2.8
141923	122	118	131	140

Embodiment 7: in primary hepatocyte to the Antisense Suppression of PCSK9

In people's primary hepatocyte, tested the Antisense Suppression of the antisense oligonucleotide of target PCSK9 to PCSK9.People's primary hepatocyte is available from commercial supplier, and cultivates flow process according to routine and cultivate.With cell with 10,25,50,150 or the antisense oligonucleotide of 300nM handle 24 hour time period, separated RNA thereafter, and measured PCSK9mRNA by PCR in real time, as described herein.

The antisense oligonucleotide of testing in people's primary hepatocyte is Isis 395152,395155,395165,395185,399819,399821,399916,399954,399978 and 399992.In people's primary hepatocyte, described antisense oligonucleotide suppresses PCSK9 in the dose-dependently mode.

With 10,25,50,150 or the antisense oligonucleotide of the target PCSK9 of 300nM concentration handled the primary hepatocyte of monkey similarly.The antisense oligonucleotide of testing in the primary hepatocyte of monkey is Isis395152,395155,395165,395185,399819,399821,399916,399954,399978 and 399992.In these antisense oligonucleotides each is all complementary fully with the PCSK9 nucleic acid of monkey.In the primary hepatocyte of monkey, described antisense oligonucleotide suppresses PCSK9 in the dose-dependently mode.

Embodiment 8: in primary hepatocyte to other Antisense Suppression of PCSK9

In people's primary hepatocyte, tested the Antisense Suppression of the antisense oligonucleotide of target PCSK9 to PCSK9.People's primary hepatocyte is available from commercial supplier, and cultivates flow process according to routine and cultivate.With cell with 10,25,50,150 or the antisense oligonucleotide of 300nM handle 24 hour time period, separated RNA thereafter, and measured PCSK9mRNA by PCR in real time, as described herein.

The antisense oligonucleotide of testing in people's primary hepatocyte is Isis 395165,395185,395186,395187,405879,405881,405891,405988,405994 and 406008.In people's primary hepatocyte, described antisense oligonucleotide suppresses PCSK9 in the dose-dependently mode, and is as shown in Table 23.

Table 23: the dose-dependently that people PCSK9mRNA expresses in people's the primary hepatocyte reduces

ISIS number	10nM	25nM	50nM	150nM	300nM
						395165	16.2	20.2	22.5	48.7	76
395185	15.7	25.5	52.6	42.9	74.5
						395186	19.9	21	34.4	58.3	123.8
395187	21.1	17.4	29.7	43.5	98.7
						405879	47.7	48.4	64.9	176.6	119.2
405881	79.3	22.3	49.5	115.3	222.4
						405891	48.7	86.9	73.9	138.7	169.9
405988	43.8	43.9	67.8	105.4	85.2
						405994	10.5	24.6	43.5	83.3	95.7
406008	32.4	41.7	116	101.7	155

Embodiment 9: in the Cyno primary hepatocyte to the Antisense Suppression of PCSK9

In people's cyno primary hepatocyte, tested the Antisense Suppression of the antisense oligonucleotide of target PCSK9 to PCSK9.People's Cyno primary hepatocyte is available from commercial supplier, and cultivates flow process according to routine and cultivate.With cell with 10,25,50,150 or the antisense oligonucleotide of 300nM handle 24 hour time period, separated RNA thereafter, and measured PCSK9mRNA by PCR in real time, as described herein.

The antisense oligonucleotide of testing in people's primary hepatocyte is Isis 395165,395185,395186,395187,405879,405881,405891,405988,405994 and 406008.In people's primary hepatocyte, described antisense oligonucleotide suppresses PCSK9 in the dose-dependently mode, and is as shown in Table 24.

The PCSK9mRNA of dose-dependently suppresses in the table 24:Cyno primary hepatocyte

ISIS number

300nM

150nM

50nM

25nM

10nM

395165	36.3	29.9	14.9	8.6	3.2
						395185	65.0	31.9	35.1	16.6	12.0
395186	65.8	42.3	21.6	23.3	16.7
						395187	61.3	32.9	13.2	7.7	9.02
405879	24.3	21.9	7.7	7.1	3.0
						405881	75.0	33.5	26.5	11.2	4.9
405891	52.4	24.8	11.2	10.8	6.7
						405988	59.4	23.7	22.5	10.7	8.2
405994	64.8	52.7	22.2	7.9	6.5
						406008	56.3	28.2	26.5	13.4	13.3

Embodiment 10: in external Antisense Suppression to mouse PCSK9

Design the antisense oligonucleotide of targeted mouse PCSK9, and assessed they reduce PCSK9mRNA in former generation mouse liver cell ability.

With former generation mouse liver cell dosage be 50,150 or the antisense oligonucleotide of 300nM handle 24 hour time period.Use

The RNeasy separating kit has separated RNA, and (Invitrogen, Carlsbad CA) have carried out quantitative PCR in real time to use commercially available reagent.Use mouse PCSK9 primer probe groups to measure the PCSK9mRNA level, and be normalized to G3PDH mRNA level and/or Level.

ISIS 394814 (GAGCAACTTCGGAGGCAGC, SEQ ID NO:456) is accredited as the potent inhibitor of mouse PCSK9.With after the former generation mouse liver cell incubation 24 hours, the ISIS 394814 of 25nM concentration makes PCSK9mRNA produce 50% reduction (being that IC50 is 25nM) on the PCSK9mRNA level.Do not observe influence to the culturing cell viability.

Embodiment 11: at the hyperlipemia animal model: in the mouse of higher fatty acid nursing, to the Antisense Suppression of PCSK9

Handle

Adopt the C57BL/6 mouse fed with higher fatty acid recipe animal model routinely as hyperlipidaemia, and atherosclerotic animal model.Thereby, in order to assess the PCSK9 Antisense Suppression, in the C57BL/6 mouse of feeding with higher fatty acid recipe, assessed ISIS394814 in vivo to the effect of serum lipid level.The C57BL/6 mouse in age in 4-5 week obtains from Jackson Laboratory, and keeps comprising the diet of 60% fat.The treatment group of every group of 5 mouse is as follows: a group of handling with ISIS 394814; Control group with brine treatment; With with the control group of not handling with any known sequence complementary oligonucleotide (ISIS141923).Oligonucleotide or salt solution intraperitoneal are used, weekly twice, continue time period in 6 weeks; Oligonucleotide dosage is 50mg/kg.After the processing phase, collect whole blood and be used for the serum parameters analysis, and collect complete liver and be used for RNA analysis, protein analysis and Histological assessment.Statistical study comprises carries out the two tail t checks of distribution free relatively (nonparametric, two-tailed t-test comparison) with laboratory sample (ISIS 394814) and control sample (salt solution or control oligonucleotide).

RNA analyzes

Separate liver RNA and be used for PCR in real time analysis to PCSK9, LDL-acceptor and apolipoprotein B mRNA level.Caused the reduction of PCSK9mRNA level 92% with the processing of ISIS 394814, and the mouse of handling with ISIS 141923 or do not observe the remarkable reduction of PCSK9mRNA level in the mouse of brine treatment.The Antisense Suppression that PCSK9 is expressed is the mRNA level of remarkably influenced liver LDL-acceptor or liver apolipoprotein B not.

Protein analysis

Carried out immunoblotting and assessed of the effect of PCSK9 Antisense Suppression ldl receptor protein and apolipoprotein B level.To carrying out electrophoresis from the isolating protein of the liver of mouse, be transferred to polyvinylidene fluoride film, detect with anti-mouse ldl receptor antibody and removing acceptor B1 (SR-B1) antibody again.Mice plasma is carried out electrophoresis similarly and used anti-mouse apolipoprotein B antibody to carry out immunoblotting.Use with two of peroxidase conjugated resist detect one anti-.(AmershamBiosciences UK) makes the protein band video picture, and uses ImageQuant to use ECL to add Western trace detection kit ^TMAnalysis software (MolecularDynamics, Santa Clara, CA) quantitative.

Although ldl receptor mRNA level is not subjected to remarkably influenced, caused liver ldl receptor protein level with respect to the 141923 about 2 times increases of handling of contrast to the Antisense Suppression of PCSK9.Do not observe the proteic variation of SR-B1.In addition, with respect to the contrasts with 141923 processing, serum apoB-100 level has significantly reduced by 50%.With respect to the contrasts with 141923 processing, serum apoB-48 level has significantly increased about 3 times.With respect to 141923 contrasts of handling, do not observe the proteic noticeable change of apoA-I.

Also measured the mRNA level of rna editing enzyme apobec-1.Produce the rna editing of apoB-48 in liver that Apobec-1 is responsible for mouse and the intestines.People's apobec-1 only expresses in intestinal cells, so these cells are the sources of apoB-48 among the mankind.Compare with contrast, caused mouse liver apobec-1mRNA level to increase about 2.7 times the Antisense Suppression of PCSK9 with brine treatment.

Serum lipid is analyzed

(Hitachi Olympus AU400e, Melville NY) have measured the plasma concentration of total cholesterol, LDL-C, HDL-C, free cholesterol, tri-glyceride, glucose, ketone, transaminase and phosphatide to use the automatization clinical chemistry analyzer.The distributional analysis of serum lipoprotein and cholesterol (profiling) is as (＞Lipid Res. such as Crooke, 2005,46,872-884) described, use Beckman System Gold126HPLC system, the freezing automatic sampler of 507e, 126 photodiode array detectors (BeckmanInstruments, Fullerton, CA) and Superose 6HR 10/30 post (Pfizer, Chicago IL) carries out.In wavelength measurement HDL, LDL and the VLDL fraction of 505nm, and calibrate test kit (Sigma) with cholesterol and verify.

Using of ISIS 394814 caused total cholesterol to reduce by 52% (salt solution, 183mg/dL ± 18; ISIS 141923,194mg/dL ± 14; ISIS 394814,87mg/dL ± 19, p＜0.005), and LDL-C reduces by 36% (salt solution 22mg/dL ± 4; ISIS 141923,25mg/dL ± 2; ISIS394814,14mg/dL ± 2, p＜0.005).The free serum cholesterol has reduced by 25% (salt solution 41mg/dL ± 10; ISIS 141923,58mg/dL ± 3; ISIS 394814,31mg/dL ± 5, p＜0.005), and phosphatide has reduced by 54% (salt solution, 354mg/dL ± 29; ISIS 141923,383mg/dL ± 21; ISIS 394814,169mg/dL ± 35, p＜0.0001).HDL-C has also reduced about 54% (salt solution, 183mg/dL ± 18; ISIS 141923,194mg/dL ± 14; ISIS394814,87mg/dL ± 19; P＜0.0001).The minimizing of LDL and HDL lipid has been confirmed in the HPLC distributional analysis.

The liver tri-glyceride is analyzed

Measured the liver triglyceride content according to the normal experiment flow process, for example, abideed by by Desai etc., Diabetes, 2001, the flow process that 50:2287-2295 describes.

To making the liver triglyceride content reduce about 65% (p=0.01) in 6 weeks of PCSK9 Antisense Suppression with respect to saline control.After 141923 handle, do not observe the variation that significance,statistical is arranged in the liver triglyceride content.

Thereby an embodiment is to reduce the method for LDL-C level by the antisense oligonucleotide of using target PCSK9 nucleic acid.Another embodiment comprises the method for coming reducing total cholesterol by the antisense oligonucleotide of using target PCSK9 nucleic acid.Another embodiment is to reduce the liver tri-glyceride by the antisense oligonucleotide of using target PCSK9 target nucleic acid.

Embodiment 12: in LDL-R defective type/apoB-100 animal to the Antisense Suppression of PCSK9

Defective type/the apoB-100 animal is not expressed the LDL-R gene to ldl receptor (LDL-R), and the apoB that only expresses the apoB-100 form.Use the PCSK9 antisense oligonucleotide to LDL-R defective type/apoB-100 mouse, thereby be evaluated at the effect of Antisense Suppression PCSK9 in the situation that lacks LDL-R.Make the mouse in age in the 4-5 week mouse recipe that maintains the standard.The treatment group of every group of 5 mouse is as follows: a group of handling with ISIS 394814; Control group with brine treatment; With with the control group of not handling with any known sequence complementary oligonucleotide (ISIS 141923).Oligonucleotide or salt solution intraperitoneal are used, weekly twice, continue time period in 6 weeks; Oligonucleotide dosage is 50mg/kg (amounting to 100mg/kg/wk).Described in relevant C57B1/6 research liver mRNA being carried out the PCR in real time promoting circulation of blood sorting of going forward side by side analyses.

With respect to saline control, make the PCSK9mRNA of liver reduce about 90% to the Antisense Suppression of PCSK9.Yet, do not observe the reduction of serum cholesterol.In these mouse, the liver triglyceride level is not subjected to the influence of Antisense Suppression PCSK9.Observed liver apobec1 mRNA level and increased by 80% with respect to saline control.These Notes of Key Datas, the LDL-R of performance function comes reducing cholesterol and liver tri-glyceride needed by the PCSK9 Antisense Suppression.

Embodiment 13: in the mouse primary hepatocyte to the Antisense Suppression of PCSK9

The antisense oligonucleotide of having tested target PCSK9 in the mouse primary hepatocyte to the Antisense Suppression of PCSK9.The mouse primary hepatocyte is available from commercial supplier, and cultivates flow process according to routine and cultivate.With cell with 6.25,12.5,25,50,100 or the antisense oligonucleotide of 200nM handle 24 hour time period, separated RNA thereafter, and measured PCSK9mRNA by PCR in real time, as described herein.

The antisense oligonucleotide of testing in the primary hepatocyte of mouse is Isis 395165,395185,395186,395187,405879,405881,405891,405988,405994 and 406008.Described antisense oligonucleotide has suppressed PCSK9 in the dose-dependently mode in the primary hepatocyte of mouse, as shown in Table 25.

Table 25: the PCSK9mRNA of dose-dependently suppresses in the mouse primary hepatocyte

ISIS number	200.0nM	100.0nM	50.0nM	25.0nM	12.5nM	6.25nM
							395165	95.2	94.9	81.7	66.3	57.5	29.9
395185	109.2	100	90.5	81.2	64.7	35.8
							395186	101.9	91.5	77.8	59.1	39.5	13.7
395187	102.4	96.1	83.9	66.4	40	15.3
							405879	107.3	97.5	87.8	76.6	63	43.1
405881	104.8	102.1	98.1	84.9	68.7	48.9
							405891	104.9	103.3	101.5	88.9	79.6	49.5
405988	97.3	101.1	91.7	82.3	61.2	34.8
							405994	110.2	101	111.6	94.4	80.1	57.7
406008	99.5	91.3	83.9	73.7	61.8	39.4
							157700	97.8	98.3	96.2	94.3	83.2	76.4

141923

84.3

80

79.9

77.3

98.8

64.2

Sequence table

＜110〉ISIS Pharmaceuticals, Inc. (Isis Pharmaceuticals, Inc.)

＜120〉be used for the treatment of the method for hypercholesterolemia

<130>BIOL0090US.L4

<160>461

<170>FastSEQ for Windows Version 4.0

<210>1

<211>3636

<212>DNA

＜213〉people (Homo sapien)

<400>1

cagcgacgtc gaggcgctca tggttgcagg cgggcgccgc cgttcagttc agggtctgag 60

cctggaggag tgagccaggc agtgagactg gctcgggcgg gccgggacgc gtcgttgcag 120

cagcggctcc cagctcccag ccaggattcc gcgcgcccct tcacgcgccc tgctcctgaa 180

cttcagctcc tgcacagtcc tccccaccgc aaggctcaag gcgccgccgg cgtggaccgc 240

gcacggcctc taggtctcct cgccaggaca gcaacctctc ccctggccct catgggcacc 300

gtcagctcca ggcggtcctg gtggccgctg ccactgctgc tgctgctgct gctgctcctg 360

ggtcccgcgg gcgcccgtgc gcaggaggac gaggacggcg actacgagga gctggtgcta 420

gccttgcgtt ccgaggagga cggcctggcc gaagcacccg agcacggaac cacagccacc 480

ttccaccgct gcgccaagga tccgtggagg ttgcctggca cctacgtggt ggtgctgaag 540

gaggagaccc acctctcgca gtcagagcgc actgcccgcc gcctgcaggc ccaggctgcc 600

cgccggggat acctcaccaa gatcctgcat gtcttccatg gccttcttcc tggcttcctg 660

gtgaagatga gtggcgacct gctggagctg gccttgaagt tgccccatgt cgactacatc 720

gaggaggact cctctgtctt tgcccagagc atcccgtgga acctggagcg gattacccct 780

ccacggtacc gggcggatga ataccagccc cccgacggag gcagcctggt ggaggtgtat 840

ctcctagaca ccagcataca gagtgaccac cgggaaatcg agggcagggt catggtcacc 900

gacttcgaga atgtgcccga ggaggacggg acccgcttcc acagacaggc cagcaagtgt 960

gacagtcatg gcacccacct ggcaggggtg gtcagcggcc gggatgccgg cgtggccaag 1020

ggtgccagca tgcgcagcct gcgcgtgctc aactgccaag ggaagggcac ggttagcggc 1080

accctcatag gcctggagtt tattcggaaa agccagctgg tccagcctgt ggggccactg 1140

gtggtgctgc tgcccctggc gggtgggtac agccgcgtcc tcaacgccgc ctgccagcgc 1200

ctggcgaggg ctggggtcgt gctggtcacc gctgccggca acttccggga cgatgcctgc 1260

ctctactccc cagcctcagc tcccgaggtc atcacagttg gggccaccaa tgcccaagac 1320

cagccggtga ccctggggac tttggggacc aactttggcc gctgtgtgga cctctttgcc 1380

ccaggggagg acatcattgg tgcctccagc gactgcagca cctgctttgt gtcacagagt 1440

gggacatcac aggctgctgc ccacgtggct ggcattgcag ccatgatgct gtctgccgag 1500

ccggagctca ccctggccga gttgaggcag agactgatcc acttctctgc caaagatgtc 1560

atcaatgagg cctggttccc tgaggaccag cgggtactga cccccaacct ggtggccgcc 1620

ctgcccccca gcacccatgg ggcaggttgg cagctgtttt gcaggactgt atggtcagca 1680

cactcggggc ctacacggat ggccacagcc gtcgcccgct gcgccccaga tgaggagctg 1740

ctgagctgct ccagtttctc caggagtggg aagcggcggg gcgagcgcat ggaggcccaa 1800

gggggcaagc tggtctgccg ggcccacaac gcttttgggg gtgagggtgt ctacgccatt 1860

gccaggtgct gcctgctacc ccaggccaac tgcagcgtcc acacagctcc accagctgag 1920

gccagcatgg ggacccgtgt ccactgccac caacagggcc acgtcctcac aggctgcagc 1980

tcccactggg aggtggagga ccttggcacc cacaagccgc ctgtgctgag gccacgaggt 2040

cagcccaacc agtgcgtggg ccacagggag gccagcatcc acgcttcctg ctgccatgcc 2100

ccaggtctgg aatgcaaagt caaggagcat ggaatcccgg cccctcagga gcaggtgacc 2160

gtggcctgcg aggagggctg gaccctgact ggctgcagtg ccctccctgg gacctcccac 2220

gtcctggggg cctacgccgt agacaacacg tgtgtagtca ggagccggga cgtcagcact 2280

acaggcagca ccagcgaagg ggccgtgaca gccgttgcca tctgctgccg gagccggcac 2340

ctggcgcagg cctcccagga gctccagtga cagccccatc ccaggatggg tgtctgggga 2400

gggtcaaggg ctggggctga gctttaaaat ggttccgact tgtccctctc tcagccctcc 2460

atggcctggc acgaggggat ggggatgctt ccgcctttcc ggggctgctg gcctggccct 2520

tgagtggggc agcctccttg cctggaactc actcactctg ggtgcctcct ccccaggtgg 2580

aggtgccagg aagctccctc cctcactgtg gggcatttca ccattcaaac aggtcgagct 2640

gtgctcgggt gctgccagct gctcccaatg tgccgatgtc cgtgggcaga atgactttta 2700

ttgagctctt gttccgtgcc aggcattcaa tcctcaggtc tccaccaagg aggcaggatt 2760

cttcccatgg ataggggagg gggcggtagg ggctgcaggg acaaacatcg ttggggggtg 2820

agtgtgaaag gtgctgatgg ccctcatctc cagctaactg tggagaagcc cctgggggct 2880

ccctgattaa tggaggctta gctttctgga tggcatctag ccagaggctg gagacaggtg 2940

cgcccctggt ggtcacaggc tgtgccttgg tttcctgagc cacctttact ctgctctatg 3000

ccaggctgtg ctagcaacac ccaaaggtgg cctgcgggga gccatcacct aggactgact 3060

cggcagtgtg cagtggtgca tgcactgtct cagccaaccc gctccactac ccggcagggt 3120

acacattcgc acccctactt cacagaggaa gaaacctgga accagagggg gcgtgcctgc 3180

caagctcaca cagcaggaac tgagccagaa acgcagattg ggctggctct gaagccaagc 3240

ctcttcttac ttcacccggc tgggctcctc atttttacgg gtaacagtga ggctgggaag 3300

gggaacacag accaggaagc tcggtgagtg atggcagaac gatgcctgca ggcatggaac 3360

tttttccgtt atcacccagg cctgattcac tggcctggcg gagatgcttc taaggcatgg 3420

tcgggggaga gggccaacaa ctgtccctcc ttgagcacca gccccaccca agcaagcaga 3480

catttatctt ttgggtctgt cctctctgtt gcctttttac agccaacttt tctagacctg 3540

ttttgctttt gtaacttgaa gatatttatt ctgggttttg tagcattttt attaatatgg 3600

tgacttttta aaataaaaac aaacaaacgt tgtcct 3636

<210>2

<211>29001

<212>DNA

＜213〉people

<400>2

acgttttaaa aaaaacattt tcatgtaaat ttaaaaaaat tgaacattca cacaaaaaga 60

tgccccctcc cttgcaaaaa agagtatgcc cgttcaaaat gttgaaatgt acactcacag 120

caatggtggc tgcagactcc aagtttctga ggttggagaa ggtagccagg gagcataaaa 180

gtgagttcta tctactcatt cagtctatga ggggaaggca atggctagaa aagcattttg 240

agggacagta aaagtggcat ttttagaggg aggaagcctt gaggatgctt gtggggtgaa 300

gggaaagaat aactcaggaa gaggcattta gggataagag gaggagagga gatagtggag 360

gtaggtgatc cctgcggagg ccagattggg gcaggggagt gtcagctgag tataagagga 420

tggtcccctc tgccctgaag gaggaaggca ggaggggaaa aggatgggtg ttgacccaga 480

aagcacttgt ggtggagggg aggccccaga agaggcttct gacttaccct gattgctggt 540

acctctcagg ggagctggct gcttatttgc tggccagggt gtgggggaac ccatttgaga 600

agagggagaa ggtgacacaa ttcctttggg caacttatgg gaggggtaat tggtgaggga 660

tgaaagccct gccaagtggc aggaggccca gctggggctg cccctcataa gagtgcagtg 720

gaggatatgg gatgagaagt gactgcccct ctggttccat ctgtcgcaga gcccagggtg 780

cttccttcct cccccacctc cctcagaaca cacccactgc atgctggaca gcagccccct 840

tcctgggcct ggggacatcc atgtccctct gtgcacaggc ttcatcattc tctgggtgca 900

cggtaacgac cccggtaggt gagaggccaa ggtcccaaag gggagcagca gggaaagtta 960

gctcccatct attcttgctc caggggaggc ctttgatgag gaagctgcca aaagcacatt 1020

gcaaatacaa ttccaattac aggcaacagg aaggagaacc acctctgcca cctctgtcag 1080

caaaccatga gctcctactc tgtgctgcga tggcgggctc gatggggata actctgacct 1140

tacctcatgg agtcactgtc aacccactgg ttgcactgtc tttgtgcact ggctctctgg 1200

agtgaggtct ttgcaaacaa agtggaaaga gcatcaactt tggactccag cacctagatt 1260

cagagcaggc catttcactc ggaatctgct gtgcatctgc aagggaggat cataaattcg 1320

cctttgtttc ttcccagtat cgacagccct tccagaaaga gcaagcctca tgtcatgcca 1380

catgtacaat ctgaggccag gagctctctt tccccttttc atcctcctgc ctggtacaca 1440

ataggtgttt actggatgct tgtccagttg atttcttgaa catggtgtgt aaaaggaatc 1500

tttgcaaatt gaatcttctg gaaagctgag cttgtgccta ccatagaatt ctgaatgtac 1560

ctatatgacg tctttgcaaa cttaaaacct gaatctttgt agtataaatc ccttgaaatg 1620

catgtaggct ggacatcaaa agcaagcaat ctcttcaagg agcagctagt tggtaaggtc 1680

agtgtgcagg gtgcataaag ggcagaggcc ggagggggtc caggctaagt ttagaaggct 1740

gccaggttaa ggccagtgga aagaattcgg tgggcagcga ggagtccaca gtaggattga 1800

ttcagaagtc tcactggtca gcaggagaca aggtggaccc aggaaacact gaaaaggtgg 1860

gcccggcaga acttggagtc tggcatccca cgcagggtga gaggcgggag aggaggagcc 1920

cctagggcgc cggcctgcct tccagcccag ttaggatttg ggagtttttt cttccctctg 1980

cgcgtaatct gacgctgttt ggggagggcg aggccgaaac ctgatcctcc agtccggggg 2040

ttccgttaat gtttaatcag ataggatcgt ccgatggggc tctggtggcg tgatctgcgc 2100

gccccaggcg tcaagcaccc acaccctaga aggtttccgc agcgacgtcg aggcgctcat 2160

ggttgcaggc gggcgccgcc gttcagttca gggtctgagc ctggaggagt gagccaggca 2220

gtgagactgg ctcgggcggg ccgggacgcg tcgttgcagc agcggctccc agctcccagc 2280

caggattccg cgcgcccctt cacgcgccct gctcctgaac ttcagctcct gcacagtcct 2340

ccccaccgca aggctcaagg cgccgccggc gtggaccgcg cacggcctct aggtctcctc 2400

gccaggacag caacctctcc cctggccctc atgggcaccg tcagctccag gcggtcctgg 2460

tggccgctgc cactgctgct gctgctgctg ctgctcctgg gtcccgcggg cgcccgtgcg 2520

caggaggacg aggacggcga ctacgaggag ctggtgctag ccttgcgttc cgaggaggac 2580

ggcctggccg aagcacccga gcacggaacc acagccacct tccaccgctg cgccaaggtg 2640

cgggtgtagg gatgggaggc cggggcgaac ccgcagccgg gacggtgcgg tgctgtttcc 2700

tctcgggcct cagtttcccc ccatgtaaga gaggaagtgg agtgcaggtc gccgagggct 2760

cttcgcttgg cacgatcttg gggactgcag gcaaggcggc gggggaggac gggtagtggg 2820

gagcacggtg gagagcgggg acggccggct ctttggggac ttgctggggc gtgcggctgc 2880

gctattcagt gggaaggttc gcggggttgg gagacccgga ggccgaggaa gggcgagcag 2940

agcactgcca ggatatcctg cccagatttc ccagtttctg cctcgccgcg gcacaggtgg 3000

gtgaaggagt gaatgcctgg aacgtactgg gaactgcacc aggcacagag aaagcgggct 3060

tgccattata gtgggttccg atttggtttg gaaaacatgg gcagcggagg gtggagggcc 3120

tggagagaag gccctacccg agacaggggc ggggtgggaa ggacggcaga tgctgggagc 3180

acgaggcaat ttctttatga cacagaactc atgctctagt attccatctg tttcagccga 3240

agaaaagaac cagctgaagg ggcaggggag aaggggcgga ggtattctcg aggcccattg 3300

gcgtccttta ggactcaggc agggaagggc ccttggtgct ctggagccgg aggtggtgcg 3360

cctggtactg ggaccccgga gctgagcccg gcgcctcagc ccacctggct gtctgccgac 3420

cgtgtgcggg gcgagtttgc tcaacaactc tgccagcttc tggccctcag gctgtgggaa 3480

gcttcttccc ggggcgagac cactagcttt ttctaagtat taccagccca ggacttggct 3540

gaggttctgt gtcccccagc ttggagtcag atgtggggtt gaatcttggc ttcctctcac 3600

tagctgtggt gcttgacaag tcacttatcc ttgagcctcc attgcctaat ctttaaaagg 3660

gaggtgacaa tcgtccctac ggctcagtgg cagcagatgg ggagatgaag ggaaagttct 3720

gttgaccatg agtgaactta caatgcaagc cccgggggga tcacttgcag ttttgtccct 3780

gtctgcagtg tgacctgttg gtgacattgt ctttgctcca aaccacagct cctggggcag 3840

aggggaaaat tctgccactc acagctgcct gcccacgctt ctgtctgagt gtgctgggtg 3900

gcaggatggc aagtccttac tcagctcagt atagccctct tccttgttcc ctgagccttt 3960

gactttctcg agggatgttg tggggttgtg gccaggataa gaaagggcat ttcaagttac 4020

cactgctcca aaacaactgt tctggaaata gtgagtaccc catcctgaga ggtgagtaag 4080

cagaggctgt atgaccacct gaaccaagcc cttgaggatg tttcttctct ggtggaagtt 4140

tggaacagga gcctcctcaa gttcatttat tcattcattc aatggttatt ttgtgggaat 4200

cgaatttaga atgaaaatat tttttggcaa gcagaaaata atttttagac caatcctttt 4260

cttttagtca tgagaaactg aggcccagag agaggaggtc accccaggtg cattagaact 4320

gggtttccag aactgacact ccactgcaca gagtactctc ccaattcatt caatttttat 4380

ttagcggaag gcattttcag atgggtcttt gaagcattag taggagttca gcgatgatgg 4440

tgtcatgaga attttattct aggattagga ggtaccatga acaaagatac agagctggga 4500

aaaccagagg tggaagataa ggagcacatg tccacagttc tttttctttt ttttttgaga 4560

tggagtttcg ctcttgttgc ccaggctgga gtgcaatggt gcagtctcag ctcactgcaa 4620

catctgtctc ccgggttcaa gtggttctcc tgcctcagcc tcccaagaag ctgggattac 4680

aggtacctgc caccacgccc ggctaatttt tgtattttta gtagagaagg ggtttcacca 4740

cgttggccag gctagtcgca aactcctgac ctcctcagtg gatccgagga ggtgatcctc 4800

ccgcctcagc ctcccaaagt gctcgaatta caggtgtgag ccaccacgcc tggcctccac 4860

agttctttat ccaccgtctg aaatgtaaaa tgttacgaaa accaaaagtt ttttttgtga 4920

tttatttgat ggtagcacct gacgtgaact gacatgagat tatttttaat ttagttgtgt 4980

gaatatgcat attcatatat tttgctgcat agattacagt atgcagctcc agattcttcc 5040

aagcagactc tgattgccca ttactgcctt tctaaaatcc aaacaagttc tgaggttcaa 5100

aaccgttttg gccctaaggc tttgggtaaa gggggtggac tctgttctac tctgactgga 5160

gtccaagatg catatataca gagatatggg tgatggggct gcaaggtagg ttgaggtagg 5220

ggccaaggag gagcatggag tttggacttg attcatgagg ctgtggggag ccagtgaagg 5280

ttcttaagca ggtatgtctg cctgagagca gttggagcag acaagagcta aaaaccaaac 5340

aaatcaccat agatagtggc tgctataatt tgtttgtccc ctccaaatct catgtggaaa 5400

tttggtcctc agtgttggaa gtggggccta atgggaggtg tttgggtcat gggggaggaa 5460

cccctgtgaa aggcttggtg ccgtccttgt gataatgagt aagttctccc gctatgattt 5520

cccttgaagg ctgattatta aaaagagctt ggcacctccc tctcttctct cttgcttctt 5580

ctcttgccat gtgattgatc tctgcacatg taggctcccc ttcaccttct gccatcagtg 5640

aaagcagctt aaggccctca ccagaagcag atgctggtgc catgcttcct ggagagcttg 5700

cagaatcatg agctgaataa atcccttttc cttgtaaatt actcaccttc aggtattcct 5760

ttatatagca acacaaaagg actaagacag tggccttgac ttttctctct ctttaagaag 5820

tgttgccttt gctcacttag tcatcccttc tgcctgcatt tgtagagcat ctggatggga 5880

gatttatata accgtcactc ttgactttcc cagcaggcct atgtcatagg tactgtggtc 5940

tctacaatac agcagaggta tctgaggctc cgagaggttg agtgacttgc tcatggctgc 6000

acaaccagta aatattggag ctggaattca ggtccacggt ttcctggctc caaagcccat 6060

gattttttcc ctcaatttat tctgactggg gcatggggga gggggtggcc tttgggcagg 6120

gccaccagga gcgaccaggc ccgtagagag ctgggtgcag gtacagagga aaacctgttg 6180

tcgagtgtgg cccgtagttc ccatttttgc ctgaatggca catttgaaag tgttatataa 6240

ccatgtgaat aataatagtt ggcctatatg agttctttaa tttgcttttt ggtccgcatt 6300

tggtaacttc tttatcatct actatactct gttgtgtctc ttttgttgta atttgtaagt 6360

aggggtgaga taaagtacac ctagggtttg ctgggtttct tccatgtcat catgttcctc 6420

cttgcatggg gccaggatcc gtggaggttg cctggcacct acgtggtggt gctgaaggag 6480

gagacccacc tctcgcagtc agagcgcact gcccgccgcc tgcaggccca ggctgcccgc 6540

cggggatacc tcaccaagat cctgcatgtc ttccatggcc ttcttcctgg cttcctggtg 6600

aagatgagtg gcgacctgct ggagctggtg agccaccctt tttgggaatg gcacttcctg 6660

atagggctgg gccactgcat atacactggg gactgtgctt agtaggccca ttgctgaaaa 6720

tcagaagggg acagcaagta tgtattgagc acttatcggg taccaagcac agtaactact 6780

ggctttctgt atagaattcc ctttaagcct ggccatgccc cagtggtacg tctatcttca 6840

tttgaaagac gaggagactg aagttcagag gggaccacac agacagctag gggtagagcc 6900

tggatcaaac ccattggtct gcctgccagc cattcttgtg ccaatgcatc tgctgcctac 6960

ggaaacctgt agggacaagg ccctgggatg ttcagtggag cctgagtcat tttataaaaa 7020

agcatgactc tagggtccaa aattcctttg aagctgttgc tatccagagt gaagtccctt 7080

ctttaggaca gggtggccct cctccctcct ggatgtcaca tcttcggtgg aggggcagaa 7140

aggggactgg gtattctcct caccctggcc ctagtgcttc aaatcttaaa aaaacgtttt 7200

tatttgtgct tctgcaccac cttctagccc acctcgtttc ctggcctcta acttgatgag 7260

agcgtgtgtc attttcacac tgattctcca catggcaggc ggtgcttctt agcctcctgc 7320

agacagtgag gccccacggt cttgtccaag gtcacacagc gtgtaatggg cagggtcaga 7380

gtctggagtc tggacctggg tctcctagct gcactgcact gctgccccat gggttaatca 7440

gctcagcata ccgtggctga acagctacct cataccaagg cctgtggcgc catgacaggg 7500

attgacaggg tccctgcctt ggaaacccgt agtctaagta gaggagactg acaagtcaat 7560

gccttccatc agtctgctca acacacgttt accaagtgcc tactgtgtgc tgcagaggcg 7620

aagatgacac agctcaggcc tttcccttga gcttacagtt caggaggaga gactgaccag 7680

tgactgccag tacagttgac tatgggacaa tgtgctcagc cttggggaga gacgaagaag 7740

gtacccgtat agcaccagat gacaggcacg agccccacag gccagggcag ctgctcagag 7800

gagagtaggc caagcagaag gcagacagaa ggctgcaggc atttgccatc gagagctgga 7860

cttcaaactg ggcatcatac cagcctgggt tcgagtcctg cccagcccct tattggctgt 7920

ctaaccctga gcaaatccct tcacctctct gagcctcatt cctctatctg taaaccagtt 7980

ataataattg gaacattcat ttaaggacta aatgaggtcg tgaagcattc agcagatgct 8040

aggtacggaa actcgctgaa gtgggggcag gttaagaagc ctctggggat acgaaggcat 8100

ccagggacta gttgtggcag gaggctgtta ccacttaggt ctgaagggta aggagaggga 8160

atagctttcc ctctgcccag ttggagccgg tggcatggag gagaggctgc ctgtggggaa 8220

tcacccgagg gttcaccgct gccatgcgca gggagtcagg aggtagggag ggagtggggc 8280

agatgcacac catttttttt tttttttgag actctgttgc ccagactgga gtgcagtggt 8340

gccatatctg cacctctgcc tcccgggttc aagctcactg caacctctgc ctcccgggtt 8400

caagcgattc tcctgcctca gcctcccgag tagctgggac tacaggtgtg tgccaccatg 8460

cctggctaat ttttgtattt ttaatagaga tggggtttca ccatgttggc caggctggtc 8520

tcgaactctc gacctcaggt gatcccccac ctcggcctcc caaagtgctg ggattacagg 8580

cgtgagtcac cgctcccagc tgctgatgca ctcttgtcct tctaactcct gctagtgcct 8640

cccattggct gagcccaact ggaagctttg caagggagct ggtgctgcag tttgcactga 8700

gcaggctgga gaaggctgga gaatagacta ggggacaaac cgaattgcca gtgctgttat 8760

gtcatgattt aggcatggag tccagggcct gagcttcact ccatgtccat cctgcccaga 8820

gccttggcac agcctggctc ccagacaaga tgtcaagttc agaatccttc ctaaaaggaa 8880

tcctctatgc cagaccgtgt tgcagggata tgggagtgct gggctcccag cctgatcaag 8940

gagcgagaaa actcaggctc ctagtctgtc ctccggggca ctagcaggga caaggtggga 9000

ggctgctggg ctgggatgtg gggacaggtt tgatcaggta aggccaggct gtggctgtgt 9060

ttgctgctgt ccaaatggct taagcagagt cccccggcct ctctggcttc tgcaggcctt 9120

gaagttgccc catgtcgact acatcgagga ggactcctct gtctttgccc agagcatccc 9180

gtggaacctg gagcggatta cccctccacg gtaccgggcg gatgaatacc agccccccgg 9240

taagaccccc atctgtgccc tgccccaccc catctgagct gaatccattt gctctgccct 9300

ggcctggcct ccctgctggt ggtttccact tctcgggggg ctttgggact cagcacctcc 9360

actgacccct ttttttctgt cccatcccca tcccctgcag cccccactgc ctgccttcct 9420

gttgccccac aaatgcaaaa gtcttgcctt aaatgatcct cttttccttc ttttctcttg 9480

ttttcctttt ctcaccattt ggaatggccc agcaggctgc acttaccttg gaaggagggt 9540

tcatctgatg gtgactctac ctagggcccc caggcctcta taactcccag tgccctgcag 9600

actggaccag atcctttaat gggatagaca caaccctgtc tgggatgcct ctgcctacct 9660

tcctgttttg ctgctccacc tgcctccagc tccgtttggc ttcctggggc tccctgcctg 9720

ggccactttg tgtcttccct ctaggccttt ctttccactg ttccctctgc ctggtgtggc 9780

ctggctatgg aagggaggga ggaggagcgg ccatggaaaa cggtctgcat tctagcaggg 9840

acttgcaggt ggcaattcag tcggggaaga ctctagatgc acctggcctg aggagagaat 9900

gaagggttct agttggactg tgttaagttt gaggtgccca tggtgtgagg tctggagctc 9960

agcgcagaga tgatgcaatg tggtgggtcc atgcaacatg gtgccaggac gcagagcttg 10020

gggtgaactc agctttcacc ccttaccggt tctcgtggga tcttgggaag ccactttctt 10080

ctatgagctt tgtcgttctt gtctgtaaaa tgggcacata accctgtccc tgtccttctc 10140

acaggttgct gtgagactcc aatgagttga aggatgtgca gatgcttttg gaagtgaaaa 10200

gttggggggc tactgtgtga ctttgcatac acccaaactg tgtgaccttg catatgtctg 10260

agttgctgcc attgcaacag atcagagctg gtgggctggg tgtggagaaa gggtttgtgt 10320

gggggacatc ctctggcaag ggtggcagca gcagaagtga ggggcctggt cggtcatgtg 10380

tgctgacccg gcctgggcag cctgtggcca gggagaggac agctcctctg taggaagagc 10440

ctgttccttt ccaaccaggt gagacctctt cagtggagcc ctggagcccc ctgtactcca 10500

catcagtgcc tcagggacct cccggagcag gctaatatca gagaccaaga gggacactgg 10560

cagaggatca cagagacccc agtccaggca gggactgaga agatcttgcc ccctaagtta 10620

gtttcctagc actgctgtga caaattacca ccccctcggt tggaacaagt tgattctctg 10680

cagtcctgga ggccagaagc ctgaatcagt gtcggcagga ccactttctc ccggggggct 10740

ccagggagaa gcttctcttg cctcttccgt gtcccaacag cggcagcaca ccaatcccag 10800

cctctgtctt cacacagcct tctctgtgtc tctctcctct tcattgtctc ataaggacac 10860

ttgtcattgg atttagggcc cactggatcc tccaggatga tctcatgtgg ggaaccttaa 10920

ccacatctgc aaggaccctt tttccaaata aggtcacagc cacaggttgt gggggttagg 10980

atgtgagtgt atctctttgg cagccactgt tccctcctct cccttgggcc agaagcagac 11040

gtggggccct ttcttcccca taggatgccc atggattgcc ccccttcccg cttcccccga 11100

gtgtctgtgg gaggtggcag gaatggcagg caggggtgtg gaaccccttc tggagtcata 11160

tcaagggctt ggctggagga agtcctcctg gagctgttgg gctggcatgg ggcaggctgg 11220

ctgggcccag cagcagcttc ttcattcatg gggaggccac aagcatgggc cctagagctg 11280

gctgccgccc tcaaacccag accctgcact cttaactgtg tgaccttgca tacgtcactc 11340

accctctctg atcttcaggt tcctctgcaa aagggaggta atgataaccc tcactctggg 11400

gggctgtttg gagggttaaa tcagttattg ctgtagcatg catttctctg tcaggtattg 11460

agtgaggtgc tgtgatttta gccctgcatt tttcttttct taccattcaa taataacgtt 11520

ttgagcaccc actgtgcgcc aggcaccata ttaggtgctg gggatacaaa tgtgaatgaa 11580

atgaatgtgg tctcttcccc caacagtgta tccagaagat taatccattc cttaaacaaa 11640

tgctacttga cacagattag ttctggatag gctgagagct ctgaaggagt gcaggcagct 11700

gcgagcctgt gtatccagca gaaggatcag gaaaggattc ctggaggaag cgctgttcta 11760

gccaagacct acgggggcat tattaaccag gcaaagggga cggtgtccaa gcagtggaat 11820

gaacgtggat tgaagctgtg aggcaggagg gagtgtggcc tgtgcagaag ggaccgaggc 11880

tggtgagacc aggagggcct gggtggcctc caggtcagat gtgaaaggaa gaacttggcc 11940

acagtctgag cttctcaggc gtatggcagg gctgcctggt gagagggaat gagctccctg 12000

ctctggaggt atgcaagcag gactgggctc tcacctgcca gaggccacag agctttccag 12060

aggctggaag aggccactcc aaggcctctt tgcccctgag agtggtggct cttcttgagg 12120

ccaccttgcc acgctgtcac agggaactag cagcccctgc ctcacccggg ggtttggaag 12180

atagagggag gcctaggaag ggccctgtgt ctcatccgag ctgggcccct ttccagcctc 12240

tcactggaag gaagcccaag gatgttcctg tgggggcttt taccaggccc acctgccctc 12300

tgctggccat gcttgcagcc tcctgaccct gtcccagcag gacagtgggc tggtgtgagc 12360

gggcaggaac cgcctgcact tagaaggtgt ggggctgcct ccccgagctt ccatctgccg 12420

ctggggccac accccaggcc cagggatggg accccacagt ggtcacatca tcttgcagca 12480

gaacccaggt acagctcctg gagcagatgg tggtcccaag cacgggtggg accagaaagg 12540

actctcacct gggctaactc agctgcagcc tcagttccct cctcacacac gacgaggaac 12600

atggactgga agcctgccca gcaggccttc tgctcgatgt gcgttgtgtg gcttacgtcc 12660

agggagggaa gcagcctctg tgctgtcttc tagataagcc tgtattcccc gggctgtctg 12720

ccaatgtatc cagttgtccc gtcagcctgg aagctctgag ggaaaacctt gggctgcttc 12780

ctgagcacct gtatcccctg cagccagccc ggggcctctg ctaggagcag actgagcatg 12840

gcttatgggc ctggcaccat ctggcctctg cccaccttgc tggccttgtc ttgtgtctgc 12900

cccttcgaca ttccatagcc cagctcaata tctagtggtt cctctagggt ggcgagcact 12960

gtttggtctc cagatgtctt caggtcggag ctcacagcgc tctcagccac cccttcccag 13020

tgtagcaccg ggcacatggt agatgcctat tgatgagtga aagctcctaa cacactcaga 13080

gagcaaggac tccgcctcat cccacagcct gggaggagag gcagactgcc aaggacctgc 13140

tcagcatgct acagaagaaa ccaaagtgcc cacgggactg atcagtggag cttcctgccg 13200

agactggagg ccttagggca gggtagacag tgtgtgtgca ggctggggac tcacagttcg 13260

gactgtgccc agacctacta gcatagtggg tgggtgggag gatgcgggac tgggggccga 13320

ccttgcctga aattcatgtg ggatctcaga gcagccactg aattgctctg tagggggcta 13380

aatagtggcc cccacagata cacacaccca gacagagcct gtgagccaga ccttatttgg 13440

agaaaaggtc tttgtagatg taattaagca tctcaagatg gcatcatctg gattatgcgg 13500

tgggctgtaa gtcctgtgat gtgtctttat gagagaaagg cagagggaga tttgacacac 13560

acaggagggg ccacgtggag acagaggtgg agattggaga aatgtggcca caagccaggg 13620

aacaccagca gccaccagaa gccggaagac gtgaggcagg gttcttccca gagccttcgc 13680

tgctgagtct gggaatttgt gaccgaagcc ataagaagtg ggtacacgcc ctgagcctcc 13740

cacacttgct cacctgtcct gagatgagaa tctctactct gcagcatatt tggaggatca 13800

ctgcgggggc cacagaggtg ctgttcagat ggcacttcag aagactcagg agaccctggg 13860

gcaggagcag tttgactgac agcccagagg gctgccctct gattccacct gaggccctgc 13920

ttttcctggc tgcaggggtt ccagggccag gccatttccg ctggcgcagg actctgctag 13980

cagcaacctg cctgaagtct tcctttggcc tggctgagag tttctgagac ctgcgctgga 14040

gcggaggtgc ttccttcctt gcttcctttc ttcctctctc ccttctccat ccagcaggct 14100

ggacctgcct ggcatctgtg agctctccct actttctcct ataccctaac ctttgtcctg 14160

catgggcgac tcccccagtg agtctcttgc agcttttacc ccagtgcctg cttcttggag 14220

aatccaaact gatccagtta gggatgataa agtgtagggt aggcgctcgg tgactgtttt 14280

ctctgaggtt gtgactcgtg tgaggcagaa gcagtccccg tgagccctcc tggtatcttg 14340

tggagtggag aacgcttgga cctggagcca ggaggcccag acatacatcc tgtccgagct 14400

gcagcttcct gtctctaaaa tgagccggcc agcgcaggtg gccagacatc actgttattc 14460

tcctttgagt ctttaaatct tgttgtcttt cttgcagact cggtgagctg tgaaaggcta 14520

taataggggc tttattttac actttgatac tattttttga acattcatat tattgttaga 14580

tattgatatt catatgaagg agcaggatga cttgggtcct tcttggcagt agcattgcca 14640

gctgatggcc ttggacagtt acctgccctc tctaggcctc cctttccttg tctatgaaat 14700

acattataga ataggatgta gtgtgtgagg attttttgga ggttaaacga gtgaatatat 14760

ttaaggcgct ttcaccagtg cctgggatgt gctctgtagt ttctgtgtgt taactataag 14820

gttgacttta tgctcattcc ctcctctccc acaaatgtcg ccttggaaag acggaggcag 14880

cctggtggag gtgtatctcc tagacaccag catacagagt gaccaccggg aaatcgaggg 14940

cagggtcatg gtcaccgact tcgagaatgt gcccgaggag gacgggaccc gcttccacag 15000

acaggtaagc acggccgtct gatgggaggg ctgcctctgc ccatatcccc atcctggagg 15060

tgggtgggga ctgccacccc agagcgttgc agctgtactc ctgggttgca ccccccccag 15120

ctgtcactgt cccctccctg ccatcagttg tgggaagggc gttcatccat ccagccacct 15180

gctgatttgt tatagggtgg agggggggtc tttctcatgt ggtccttgtg ttcgtcgagc 15240

aggccagcaa gtgtgacagt catggcaccc acctggcagg ggtggtcagc ggccgggatg 15300

ccggcgtggc caagggtgcc agcatgcgca gcctgcgcgt gctcaactgc caagggaagg 15360

gcacggttag cggcaccctc ataggtaagt gatggcccca gacgctggtc tctctccatc 15420

tggacctggc ctgggaggtg gcttgggctg ggcccaggga gagctaatgt ctcctaacca 15480

agaatgctgt ggcagcctct gccgcagagc cagagaacca gagtgccaag gctggcaggg 15540

ttcccagtgg ccacgagtgc agatgaagaa acccaggccc caagagggtc atgcaggtag 15600

cccagggagt tcagccttga ccctgggtca atgacctttc cacagttcca cactgctccc 15660

cttttaaaat ccggtgatgt ctttatgtct tttgttatgt tatcttcaat gtggagggac 15720

tcgaggtgat ctaagcaaac tttttctatc ttctgcttgc atacctctga gaccagggga 15780

ctcactcact tgcatgactg ggccctgcag gtcacactgg ccaggcagat gtggtggagg 15840

aactggcaga ggactttttc tagactgtga ctacatttag tccacccagc ggccccccta 15900

tgaagtccag ttgagaacta ggactctggg ggccggtgga cagagaagag ggagggttct 15960

ctcccttact gacttccttc tgtggccaga cattgagcaa ggcctctgta cagcatgtcc 16020

tggggctggc cttgccgtag ctgctaaata gttgacgaaa ccagtccaga gaggggaggt 16080

gactgccagg gtcgcacagc tcaagctggg gaactcgctg ggaaaactgt cagctctggg 16140

cagcagcttg acttccactg taagccccag cccccagggt caaacactgg ctctggtgct 16200

ggcagaggca gcccactagc ctgtttcaaa ggctgagaag gcccaggagt ctgccctgtg 16260

ctccaccagt tctgccctga gactttccta cagagtacag gttttgatgt tcagttttaa 16320

aggcaagaat caataacctt ctgccccatc aggtgacccc ttgtgcctgt cccacccctt 16380

tattgactga cctcggctca gtcaggtcag ttcctgaagg tcagtgtgtg gaggggaggc 16440

tgttctttcc cagaaaggcc ttccccaggc ctggtgctct ggcctctgga ggacttcctg 16500

gagaagtccc ttctttgggg tcccagtcag tgtatgggaa gcccttattg catgacctgg 16560

cacggggcag gggctcaaca gtcactattg ccttccttgc cactgccatt tcctcctctg 16620

taagcaggtg attgtgtgtc cagtctgagc acagagataa gcacacagca ggtgcttaat 16680

aactagcagc tgtaggctgg gcgcggtggc tcatgcctgt aatcccagca ctttgggagg 16740

ccgaggtggg cagatcacct gaggtcagga gttcgagacc agcctgttca acatggtgaa 16800

accccgtctc tactaaaaat acaaaaatta gccaggcatg gtggtgggtg tctgtatccc 16860

agctacttgg gaggctaagg caggagaatc gcttgaaccc aggaggtgga ggttgcagtg 16920

agctgagatc gtgccactgc aatccagcct gagtgataga gcgagattcc atctcaaaaa 16980

taaataagta aataactagc agctgtaaat gtggctgttg ttcttcacct ccacactcag 17040

tgccactcca ctccctccct ccgtggtgtg aggggcctca ctagctgtct cctaggagga 17100

gcatggctgt gagattccag ctccatcctt ggccacggct cctggagaca tcttagaggc 17160

caggatccag aaggctccca cacctcattt gacaggggag aagctgtcag ttccaggtcc 17220

ccttgcacat cagggccaga gctgcgttag gcctccagtc tccaggccac tgggccagag 17280

ctcacaggct ggcagagggt tagaactgtt actggtggct gggtgcagtg gctcacgcct 17340

gtaatcttag cactttggga gggcaaggcg ggaggatcat gaggtcagga catcgagacc 17400

atccttgcta acacggtgaa gccccgtctc tactaaaact acaaaaaatt agccgggcgt 17460

ggtggcaggc gcctgtagtc ccagctactc aggaggctga ggcaggagaa tggcgtgaac 17520

ccgggaggcg gagcttgcag tgagccgaga ttgcgccact gcactccagc ctgggcaata 17580

gagcgagact ccgtctggaa agaaaaaaaa aaaaaagagc tgttactgtt gacagtagca 17640

tgaggtagac catggcctgc accaaaatgg gggagtggag tgccactgag gccagaagga 17700

accacaccct caagggtggg gagttatggt atggggggtc ctaggcatgg agtcttttaa 17760

ttctttagac aatcctggga gcaactgtcc ctgtttcaca gagggcgggg ccacacagct 17820

ggtgagtggg cagccaagac tctgttcaag tttgtgtggg tccaacactt gcggccacgg 17880

tggaggggca tctgagccag gcctcagaga gtggcggggg aagttgggtg gggaagtgtg 17940

cccttctcat tcctctgagg ctcatcctct tggtgcctct ctttcatgga aagggataat 18000

aaggttattg tgaggatccc ctgagttcgt atattcagac gcttagacag agccaggcac 18060

agagaagggc ccggggttgg ctagtttgat tgctggtgta attgctaata tcttccagtt 18120

tgtattggtc aaggttctgc agagaagcag aaccagtagg atgtatatat taagagtttc 18180

aagctcatgt gaccgtgcgg gctggcaagt ctgaaatccg cagggcaggc caggcaggct 18240

ggcaattcct gcagaatttg atgttgcaat actgagtcct aaggcagtcc tggggcagaa 18300

ttccttcttc cctgggaggc ctcagtctgt tctcttaagg ccttcaactg attaaatgag 18360

gcctgcccaa gttatagaga gtaacctgcc ttactccgtc ttctgattta aatgttagtc 18420

acatctaaaa aatattttcg cagcagcatt tccactggct tttgaccaaa catcaggcca 18480

caaagttgat ccccaaaatt aaccatcact ctgtgcctgt aagggagggg ctgggaaagg 18540

ggagcaggtc tccccaaggg gtgaccttgg ctttgttcct cccaggcctg gagtttattc 18600

ggaaaagcca gctggtccag cctgtggggc cactggtggt gctgctgccc ctggcgggtg 18660

ggtacagccg cgtcctcaac gccgcctgcc agcgcctggc gagggctggg gtcgtgctgg 18720

tcaccgctgc cggcaacttc cgggacgatg cctgcctcta ctccccagcc tcagctcccg 18780

aggtaggtgc tggggctgct gccccaaggc gcgggtaggg ggcggagggc ggagggcgga 18840

gggagggcgg gcgggcaggc gggcttcttg tggcacgtgg gcttcttgtg gcacgttcct 18900

ggaggccgaa cccttctggc tttggaagga gtcgtcagag acccccgcca tgcgggaggc 18960

tggggaggaa ggggctcgaa acctccatca tcgcagagtc tgaatagcag tggccccgcc 19020

atgcgcccac gtagcggcgc ctacgtagcc acgcccccac accccgtcct ggccactctc 19080

cctcctgaag gtcttctggt acccgccccc tccccatctc catccccagg ccctgcgtcc 19140

tctgcccaat actctttggg cctccctgtt gtccagctct ctccgcggct ccatgactga 19200

caacttgagc aaggctaatg tgaatgggag cggttgaggg ctcagacctc tcacccgagg 19260

aacatccaca gagtgtgccg catgcccggt gcagtgtggc tgcggggaca cagacacgga 19320

gcctcggccc tgaggagctg gggggcagtg accgtccctc ctctgaccca ccactcctcc 19380

agtgtcagga cactgcgggt atctagggga aggaatcttg ttccacttca agtctggaac 19440

ttcaagtctg tgtgtgtgcg tgcgcgcgcg cgcgttgggg gtgggggttg cagagcagat 19500

gcgtacctga cagcggtaac ctaggtcccc cctggcctat caaggcttcc ctggcggccg 19560

aatttaaagg catcaagcaa acaaagccca acacatctct gccttgtcct ctcagtttcc 19620

ccccgtggca cttagaacca cttgatacac cgaatagttt cctatctccc ccactaggat 19680

gtaaactcca caggggcatt gggaatgctg cctggctatg gtagggacag aggggagcac 19740

cagggcgggg caggggtgcc agagttctgc ctgggcagtc agattttcct taggagggga 19800

catttgagtg ggacccaaac aggtgtatag cagttgtcca gcccagctgg caaggcctga 19860

gtctgcctct gcaacccctc tcttgggctc ctttctctgc cacccacctc ctcacctttc 19920

caggtcatca cagttggggc caccaatgcc caagaccagc cggtgaccct ggggactttg 19980

gggaccaact ttggccgctg tgtggacctc tttgccccag gggaggacat cattggtgcc 20040

tccagcgact gcagcacctg ctttgtgtca cagagtggga catcacaggc tgctgcccac 20100

gtggctggta agtcaccacc ccactgcctc ggccaccgtg atgctaacag cccctttggc 20160

agtcagggtc tgtgccggga cctccagtgc caggctctgt gcagggggac cagagatgaa 20220

gtaggcctga tggtgccttc aaggacactc agtctgatga gggaggcgag tgcacagagg 20280

aaacacgagg tcagggctgt attagaggga gcccagagga ggcacctgcc cagcccgagg 20340

gtcagagaag gcatcttgga ggagggacat ttgatcggga gcttgatgga tgaataggag 20400

ttcacctggc cgataagaca gcaactacca aggcttagag gtgtgagagg aggctgtctt 20460

acctcactga gtaaggactg caggcggctt accttcgaga agagagctta gtgtctgtgt 20520

gcacgtgtgt ttgtgtgtat gtgtgtgcgt gtgtgcactg gcaggagtcc cctgctgggg 20580

caggagggcc gggccatcac catctttcac cattcacccc tgcaccaggc attgcagcca 20640

tgatgctgtc tgccgagccg gagctcaccc tggccgagtt gaggcagaga ctgatccact 20700

tctctgccaa agatgtcatc aatgaggcct ggttccctga ggaccagcgg gtactgaccc 20760

ccaacctggt ggccgccctg ccccccagca cccatggggc aggtaagcag gatggcaggg 20820

tgggcaagtc caggctgggg cttgggaggt ctgtgtgacc ttgacagtct ctcccttctc 20880

ccttgtctgt gtaaggagga tgacgccacc ttaaatagga ttaaatgaga atggggctct 20940

gaaagggctg tgcaatattt tcataacgtg tttttataga gacagttgag tatgttcttt 21000

aagccctcct ctctcctacc atgaactaaa gatttctgtg gaggtcccct cactcccagc 21060

accccctcct catcccaggc cctttttgca ggttggcagc tgttttgcag gactgtatgg 21120

tcagcacact cggggcctac acggatggcc acagccgtcg cccgctgcgc cccagatgag 21180

gagctgctga gctgctccag tttctccagg agtgggaagc ggcggggcga gcgcatggag 21240

gtgactgtac ccctccttcg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 21300

tgtgtgtgtg tcagtgctgg gccctcaggg acccccagca agcccctcca tcctccagac 21360

tccagctctt ctgtaagctt acagggctgg ccagaccagg agtggggcac tcctcacttc 21420

acgcggctgg gggctgctgg agagagccac agcgggaagg gtttcctaga ggctgcagga 21480

cagtgctgga tggattttca atgctcacct gggtgtgagc gtgcggcagg gccgcgtgag 21540

ggtcagcgat ctgctactct ggactcagcc atctctaggc ccctctcact caggtgctcc 21600

atggttctgg gagctgagaa atctcaaacc agcaaaaaag tggaattgat gttgatgcta 21660

caggatagtg cacagatgcc atctggttgc agcattttgg tggaagggca gtgcccagct 21720

aggagagtga ggaggggcag gcatttctgg cttgaggaga tggggtctta atgctcgtgt 21780

gagaggcaga gtgggtggag tggagctggc tggatccttg ctttggcctc ctggatttct 21840

ctctatctcc attttgaaac cactctgtgt ttggaagaac ttttgagtat tcagagctgc 21900

ccactggcag aacagtcttc cttgggcagg agtgagctcc ttgtccccag aaggctgggt 21960

ctggctggcc cctggcaggg acactgatga gggtgcttga gttgatcctg tctagtccct 22020

ttctgtgttt tcaaagccca ttctaaagca gattcccatt tccgtctttg actctaaggc 22080

ccaagggggc aagctggtct gccgggccca caacgctttt gggggtgagg gtgtctacgc 22140

cattgccagg tgctgcctgc taccccaggc caactgcagc gtccacacag ctccaccagc 22200

tgaggccagc atggggaccc gtgtccactg ccaccaacag ggccacgtcc tcacaggtag 22260

gaggctgggc ttgccctggg gtgaggaggg gtctctttct ccttatgcac ccactgcccg 22320

cgaggcttgg tcctcacaag tgtgatccat gagactcaag cctgacttgc agttccatac 22380

tctggttctg ccacttccat gccctttgag cctgggcagg tgaccttact tctcctcatc 22440

tcagcttcct cctccataag agggaaaaag gtattacctg cctcattgtg ttgcaaggag 22500

atgggcagca tctagggcac tggcctggag tatcgcaggt gctttgccta aggtggtgca 22560

gtccaggaga ggcagctcca gagagaggcc cccggctggg gctgaaagga gggcagacct 22620

cggtttgaat ttcaccctgc cgctctatag ctgtgtgact tgggcaaatt acttaacatc 22680

tctgtatgag gaaatgatga gtgctaagca cttagcttag tgccgggaca atataaattc 22740

tagctatcgt tactattgtt ttcatcaccc gttgctttaa aatccagcct ctggtatagg 22800

caactattga cgggctaccc tgtgtcgaaa acatgcccag gcaggtagca ggaagtcaca 22860

gatggggacc tcttggggca tcaagggatg gtgccctgag gctgagctgt tctggttggg 22920

tggagcatga gaggtctggg aagacagtgg gactccagcc tggaataaga ggctcagagt 22980

tgattctcgt ctgagcacgt ccaggggaac cactgagggt ttgggaacag gagagtgagg 23040

gtgagaacct ggttctgggc acagcaggct ggcatgtagg atggatgttc aggaaagatg 23100

agcatagtca ggtggctggt gcccttgtcc aggggagagg ctccgtcagg ttcaggggtc 23160

ctggcttgga gggaagtccg ccatgctcta atcacgctcc cctttggaag tgctcagccg 23220

atgagctcac aggcacatgt cagtttgaag tcatggaatc tgactccatg aagcgcacct 23280

caaagagcac cattttgcag ctaagggaac tgcaggctgg acatgctgag tggctgcccc 23340

gagcccttgc agctaggaca tagagaatgc tagtaaccac aaccctacca tgttcagagc 23400

acatgccagg ctccatgctg gggcttcgca cgtgtcatct tcacagtgtc cctgtgagta 23460

ggtgtggttt ctctttccat cttacaaatg agtaaacaga gcctcagtgt agctaagtaa 23520

ccactatttt aggtttctta gccaatgggt gtgtctgact cctaagccca tggagggcat 23580

tctgaggtgg ttcagacaga ccccggctta cccttgaact tctgcctgct ggctgcatag 23640

ggaggggctg gggggagttt gagcatctca ggccatagag cccctgcctc actgtctcca 23700

tctctgggtg gaaagatggt gttttccctg agaaactaag gctcagagag gttgaatggc 23760

tctcccaagg tcacacagct ggtcagctgc agagttgaga acacaggagt cctggtgctc 23820

aggccagcat ctcttttttt ctttgagttg tttctaggtt tcctagctct tgcctcagac 23880

cttaaagaga gagggtctga tggggatggg cactggagac ggagcatccc agcatttcac 23940

atctgagctg gctttcctct gccccaggct gcagctccca ctgggaggtg gaggaccttg 24000

gcacccacaa gccgcctgtg ctgaggccac gaggtcagcc caaccagtgc gtgggccaca 24060

gggaggccag catccacgct tcctgctgcc atgccccagg tctggaatgc aaagtcaagg 24120

agcatggaat cccggcccct caggagcagg tgaagaggcc cgtgaggccg ggtgggtggg 24180

gtgctgcgtg tctctcctgc acagcttttc tgtgtcagtt tgtgccacca ccataccgcc 24240

atgcatcagg gtggcggttt gccaggtaga tgctgtgggc agcttccgcc attgtgtgga 24300

cagcatgtat atgtgtctct gtgtggctgg gtctgttttt gcttttgtcc agatcagtaa 24360

ggtttgctac ctgggtaccc cactccactt ggagtagaat gtgcataaat atggcataaa 24420

gaaatgcaat atgcatgcat ttattgattg atctattttt ttctgagatg gggtcttgct 24480

gtgttgccca ggctggtctc aaattcctgg gctcaagcaa tcctctggtc tcagcctccc 24540

caagtgttgg gattataggc atgagccgct gcacctggcc tctctgatct atttaacaaa 24600

cctgctggga gggtctcagg gtcaggagca gcactgggct ctgaggacac agagctcact 24660

cagccgtgac ccagaggggg tgcctgagct gcatgctgaa ggttgttagc atgaccagca 24720

aggcaagaaa aggccctgcc gagattagca aggcatgtgc caagccctgg aatgtgacag 24780

ccgggccttc tagaaacctg agtgtataac tctccttaaa agccagtagg agctcctcaa 24840

aaggcagccc taaggagtcc actcttaaat gaactcagag tcagttttaa aatgcaagtc 24900

tgtgttgatt ctggtctgga tggtgcattc ctcgagagca aaagacagtc ttggtcttgg 24960

atccacttgc cctgggtaca ctgagggctg ctaggttcca ggtgctcttc ctggcactgg 25020

ggagggatac aggcccaaga gacatgctgt tctccctcct ggagcatcta ttttagtgga 25080

ggaagacaga aaacaaacca ttaatataga gtactgaaaa gatgcgatgg agaaaactat 25140

agcaaggaag ggaatggggt gggagagagg tcaggagagg tctcgctgac aaggtggacg 25200

aaacaggcca tgaggcagag aacatgttcc aggcaaagca aaggccccca ggtggggatg 25260

tgcagggagt accaggaaac cagagaggtg ggaatagtta tgagatgggg ggtgcctcag 25320

aggggacagg gccaagtcag gtgagacctg agggtcacag tcagcagtga gctggggcca 25380

tgcaggggtc tggcctcaga ggagtgtggt ctggcctgga tctgaacctc tcactgtggc 25440

ctagctgctg agctgagaag agatgacaag gaccttgggc agaagcaggg agactggagg 25500

gaggcggtgg agggtccagg cgttggggcg gggctcaggc tggagtctga agggagcctg 25560

caggcctggt gggtggatgt gggtgggaga gggggaggat ggcaccaagg ctcgggcccc 25620

tggacagatg gagttgccat taagtgggat ggggcaggct atggggccat cagtttcaga 25680

gggatgagtt tggcactggc atggtaggca tctgtctatc tccacggccc tcaaaccagg 25740

catgaagcag gagctcacgt gtttggtcag ccatggtgca gaaccgcctg ggtgggaggt 25800

gcggggtggg agatacacgg ttgtgtccca aatgggctct gagccagcga gggccgtctg 25860

cactttggcc tcacagaagg atgtcggagg gagaaatgaa gtgtgggtgg gggtcccggg 25920

ccacgctaga catgtgcttt cttttcctcg ggctctggca ggtgaccgtg gcctgcgagg 25980

agggctggac cctgactggc tgcagtgccc tccctgggac ctcccacgtc ctgggggcct 26040

acgccgtaga caacacgtgt gtagtcagga gccgggacgt cagcactaca ggcagcacca 26100

gcgaaggggc cgtgacagcc gttgccatct gctgccggag ccggcacctg gcgcaggcct 26160

cccaggagct ccagtgacag ccccatccca ggatgggtgt ctggggaggg tcaagggctg 26220

gggctgagct ttaaaatggt tccgacttgt ccctctctca gccctccatg gcctggcacg 26280

aggggatggg gatgcttccg cctttccggg gctgctggcc tggcccttga gtggggcagc 26340

ctccttgcct ggaactcact cactctgggt gcctcctccc caggtggagg tgccaggaag 26400

ctccctccct cactgtgggg catttcacca ttcaaacagg tcgagctgtg ctcgggtgct 26460

gccagctgct cccaatgtgc cgatgtccgt gggcagaatg acttttattg agctcttgtt 26520

ccgtgccagg cattcaatcc tcaggtctcc accaaggagg caggattctt cccatggata 26580

ggggaggggg cggtaggggc tgcagggaca aacatcgttg gggggtgagt gtgaaaggtg 26640

ctgatggccc tcatctccag ctaactgtgg agaagcccct gggggctccc tgattaatgg 26700

aggcttagct ttctggatgg catctagcca gaggctggag acaggtgcgc ccctggtggt 26760

cacaggctgt gccttggttt cctgagccac ctttactctg ctctatgcca ggctgtgcta 26820

gcaacaccca aaggtggcct gcggggagcc atcacctagg actgactcgg cagtgtgcag 26880

tggtgcatgc actgtctcag ccaacccgct ccactacccg gcagggtaca cattcgcacc 26940

cctacttcac agaggaagaa acctggaacc agagggggcg tgcctgccaa gctcacacag 27000

caggaactga gccagaaacg cagattgggc tggctctgaa gccaagcctc ttcttacttc 27060

acccggctgg gctcctcatt tttacgggta acagtgaggc tgggaagggg aacacagacc 27120

aggaagctcg gtgagtgatg gcagaacgat gcctgcaggc atggaacttt ttccgttatc 27180

acccaggcct gattcactgg cctggcggag atgcttctaa ggcatggtcg ggggagaggg 27240

ccaacaactg tccctccttg agcaccagcc ccacccaagc aagcagacat ttatcttttg 27300

ggtctgtcct ctctgttgcc tttttacagc caacttttct agacctgttt tgcttttgta 27360

acttgaagat atttattctg ggttttgtag catttttatt aatatggtga ctttttaaaa 27420

taaaaacaaa caaacgttgt cctaactctt gcatagactt gactgcctag ggtgatgcct 27480

tgcttatact aggaactggg taagtttgtt gaatagttga gtaagccaag tatttgatga 27540

gtacttttat cttgagtaca agtattgggc aagtactggt gatgtgaact tactccttgt 27600

gcctatccta ggaatgaaat gaatgtcttc ctgcagctcc cctgaccacc ctgacagtca 27660

aagtgcctcc tccttggtga caggtgccct acagcactct agatgctctg ttgtcctgac 27720

ctcccaatgc ccttttcatt cttttctccc cagtacctgg cacacagcct ggcccgagta 27780

tttacggaat aagttacagt gccagatgct tctgtaatga gccagtgcta agtccatggc 27840

ttttttcatg atttaaaatt cagaacagtc tcagattggg tgcaatggct cacacctgta 27900

atctcagtac tttgggaggc tgaggcagga ggattgcttg tgtttaggaa ttcaagaccc 27960

tgggcaacag tgagaccccg tctctataaa aaaatttaaa agattagcga ggtgtggtag 28020

cacatgcctg tggtcccggc tactcaggag gctgatatgg gaggcttgct tgagctggga 28080

ggctgagggt gcagtgagct gtaattacat catcactgca ctgcagcctg ggttacagag 28140

tgcataatga tcccattcaa tgtgggacct ccaggccctc cactctaagg ctggtgaata 28200

tagctgtctt aagcaagttc tctctctctc tagacagccc atgtcataag gaatctcagg 28260

caaaattcct cccagattac attttctgac aattcagtgt catatatgga aagcattcaa 28320

gagttgacag atggcaatgg cttgaacacc caactgtgtt atctctgccc gttggaacct 28380

aggcctgtgg tgcaacccta gactctctct ccttcccctc cacagaatca agtatcagct 28440

ggttagagat ccacaccctg acagctctgt gatgttggaa caacttggtt cttgcagagg 28500

gttagcaggt ggtcaccagg gatcggggag gaaggggtgt ggcttgcagg aaggcgaaaa 28560

tctggactag caaataggga aggggaccca tgtgagcaac gctggccact aggaatgaga 28620

ctgagacctg tgggatctag caagaagccc agtgtgacca gcgacacgat ctatgctggg 28680

gaccacttgg gagagccaaa agctttggtg gagatgaatg gagaccatca acctaagttc 28740

agcatcctcc tctaagcttt gcagatgaat cctgaaatgg tcagcccctc cagagaaaag 28800

aacagcaaca ggctcagagg acccacagtc ccctttatta gtgtaaagta ctaagaggaa 28860

tcaacagcat ttagcaccag gcacaggctc gtgttccccc gcccactacg gctgtgttct 28920

gatatatgaa gaatggcggc aagactccaa ctctgttttt gaaaaattta ttttatactc 28980

ttagaagcta agaactttgc c 29001

<210>3

<211>3891

<212>DNA

＜213〉people

<400>3

ttatgagaga aaggcagagg gagatttgac acacacagga ggggccacgt ggagacagag 60

gtggagattg gagaaatgtg gccacaagcc agggaacacc agcagccacc agaagccgga 120

agacgtgagg cagggttctt cccagagcct tcgctgctga gtctgggaat ttgttaccga 180

agccataaga agtgggtaca cgccctgagc ctcccacact tgctcacctg tcctgagatg 240

agaatctcta ctctgcagca tatttggagg atcactgcgg gggccacaga ggtgctgttc 300

agatggcact tcagaagact caggagaccc tggggcagga gcagtttgac tgacagccca 360

gagggctgcc ctctgattcc acctgaggcc ctgcttttcc tggctgcagg ggttccaggg 420

ccaggccatt tccgctggcg caggactctg ctagcagcaa cctgcctgaa gtcttccttt 480

ggcctggctg agagtttctg agacctgcgc tggagcggag gtgcttcctt ccttgcttcc 540

tttcttcctc tctcccttct ccatccagca ggctggacct gcctggcatc tgtgagctct 600

ccctactttc tcctataccc taacctttgt cctgcatggg cgactccccc agtgagtctc 660

ttgcagcttt taccccagtg cctgcttctt ggagaatcca aactgatcca gttagggatg 720

ataaagtgta gggtaggtgc tcggtgactg ttttctctga ggttgtgact cgtgtgaggc 780

agaagcagtc cccgtgagcc ctcctggtat cttgtggagt ggagaacgct tggacctgga 840

gccaggaggc ccagacatac atcctgtccg agctgcagct tcctgtctct aaaatgagcc 900

ggccagcgca ggtggccaga catcactgtt attctccttt gagtctttaa atcttgttgt 960

ctttcttgca gactcggtga gctgtgaaag gctataatag gggctttatt ttacactttg 1020

atactatttt ttgaacattc atattattgt tagatattga tattcatatg aaggagcagg 1080

atgacttggg tccttcttgg cagtagcatt gccagctgat ggccttggac agttacctgc 1140

cctctctagg cctccctttc cttgtctatg aaatacatta tagaatagga tgtagtgtgt 1200

gaggattttt tggaggttaa acgagtgaat atatttaagg cgctttcacc agtggctggg 1260

atgtgctctg tagtttctgt gtgttaacta taaggttgac tttatgctca ttccctcctc 1320

tcccacaaat gtcaccttgg aaagacggag gcagcctggt ggaggtgtat ctcctagaca 1380

ccagcataca gagtgaccac cgggaaatcg agggcagggt catggtcacc gacttcgaga 1440

atgtgcccga ggaggacggg acccgcttcc acagacaggc cagcaagtgt gacagtcatg 1500

gcacccacct ggcaggggtg gtcagcggcc gggatgccgg cgtggccaag ggtgccagca 1560

tgcgcagcct gcgcgtgctc aactgccaag ggaagggcac ggttagcggc accctcatag 1620

gcctggagtt tattcggaaa agccagctgg tccagcctgt ggggccactg gtggtgctgc 1680

tgcccctggc gggtgggtac agccgcgtcc tcaacgccgc ctgccagcgc ctggcgaggg 1740

ctggggtcgt gctggtcacc gctgccggca acttccggga cgatgcctgc ctctactccc 1800

cagcctcagc tcccgagggg aggacatcat tggtgcctcc agcgactgca gcacctgctt 1860

tgtgtcacag agtgggacat cacaggctgc tgcccacgtg gctggcattg cagccatgat 1920

gctgtctgcc gagccggagc tcaccctggc cgagttgagg cagagactga tccacttctc 1980

tgccaaagat gtcatcaatg aggcctggtt ccctgaggac cagcgggtac tgacccccaa 2040

cctggtggcc gccctgcccc ccagcaccca tggggcaggt tggcagctgt tttgcaggac 2100

tgtgtggtca gcacactcgg ggcctacacg gatggccaca gccatcgccc gctgcgcccc 2160

agatgaggag ctgctgagct gctccagttt ctccaggagt gggaagcggc ggggcgagcg 2220

catggaggct gcagctccca ctgggaggtg gaggaccttg gcacccacaa gccgcctgtg 2280

ctgaggccac gaggtcagcc caaccagtgc gtgggccaca gggaggccag catccacgct 2340

tcctgctgcc atgccccagg tctggaatgc aaagtcaagg agcatggaat cccggcccct 2400

caggagcagg tgaccgtggc ctgcgaggag ggctggaccc tgactggctg cagtgccctc 2460

cctgggacct cccacgtcct gggggcctac gccgtagaca acacgtgtgt agtcaggagc 2520

cgggacgtca gcactacagg cagcaccagc gaagaggccg tgacagccgt tgccatctgc 2580

tgccggagcc ggcacctggc gcaggcctcc caggagctcc agtgacagcc ccatcccagg 2640

atgggtgtct ggggagggtc aagggctggg gctgagcttt aaaatggttc cgacttgtcc 2700

ctctctcagc cctccatggc ctggcacgag gggatgggga tgcttccgcc tttccggggc 2760

tgctggcctg gcccttgagt ggggcagcct ccttgcctgg aactcactca ctctgggtgc 2820

ctcctcccca ggtggaggtg ccaggaagct ccctccctca ctgtggggca tttcaccatt 2880

caaacaggtc gagctgtgct cgggtgctgc cagctgctcc caatgtgccg atgtccgtgg 2940

gcagaatgac ttttattgag ctcttgttcc gtgccaggca ttcaatcctc aggtctccac 3000

caaggaggca ggattcttcc catggatagg ggagggggcg gtaggggctg cagggacaaa 3060

catcgttggg gggtgagtgt gaaaggtgct gatggccctc atctccagct aactgtggag 3120

aagcccctgg gggctccctg attaatggag gcttagcttt ctggatggca tctagccaga 3180

ggctggagac aggtgtgccc ctggtggtca caggctgtgc cttggtttcc tgagccacct 3240

ttactctgct ctatgccagg ctgtgctagc aacacccaaa ggtggcctgc ggggagccat 3300

cacctaggac tgactcggca gtgtgcagtg gtgcatgcac tgtctcagcc aacccgctcc 3360

actacccggc agggtacaca ttcgcacccc tacttcacag aggaagaaac ctggaaccag 3420

agggggcgtg cctgccaagc tcacacagca ggaactgagc cagaaacgca gattgggctg 3480

gctctgaagc caagcctctt cttacttcac ccggctgggc tcctcatttt tacgggtaac 3540

agtgaggctg ggaaggggaa cacagaccag gaagctcggt gagtgatggc agaacgatgc 3600

ctgcaggcat ggaacttttt ccgttatcac ccaggcctga ttcactggcc tggcggagat 3660

gcttctaagg catggtcggg ggagagggcc aacaactgtc cctccttgag caccagcccc 3720

acccaagcaa gcagacattt atcttttggg tctgtcctct ctgttgcctt tttacagcca 3780

acttttctag acctgttttg cttttgtaac ttgaagatat ttattctggg ttttgtagca 3840

tttttattaa tatggtgact ttttaaaata aaaacaaaca aacgttgtcc t 3891

<210>4

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>4

gcgcggaatc ctggctggga 20

<210>5

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>5

gaggagacct agaggccgtg 20

<210>6

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>6

aggaccgcct ggagctgacg 20

<210>7

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>7

acgcaaggct agcaccagct 20

<210>8

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>8

cctcggaacg caaggctagc 20

<210>9

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>9

ccttggcgca gcggtggaag 20

<210>10

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>10

ggcgggcagt gcgctctgac 20

<210>11

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>11

tggtgaggta tccccggcgg 20

<210>12

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>12

ggatcttggt gaggtatccc 20

<210>13

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>13

agacatgcag gatcttggtg 20

<210>14

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>14

atggaagaca tgcaggatct 20

<210>15

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>15

ttcaccagga agccaggaag 20

<210>16

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>16

tcatcttcac caggaagcca 20

<210>17

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>17

cctcgatgta gtcgacatgg 20

<210>18

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>18

gtattcatcc gcccggtacc 20

<210>19

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>19

ctggtgtcta ggagatacac 20

<210>20

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>20

gtatgctggt gtctaggaga 20

<210>21

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>21

gatttcccgg tggtcactct 20

<210>22

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>22

gccctcgatt tcccggtggt 20

<210>23

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>23

gtgaccatga ccctgccctc 20

<210>24

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>24

ctcgaagtcg gtgaccatga 20

<210>25

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>25

gtggaagcgg gtcccgtcct 20

<210>26

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>26

acccctgcca ggtgggtgcc 20

<210>27

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>27

tgaccacccc tgccaggtgg 20

<210>28

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>28

acccttggcc acgccggcat 20

<210>29

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>29

ttggcagttg agcacgcgca 20

<210>30

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>30

ttcccttggc agttgagcac 20

<210>31

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>31

ccaggcctat gagggtgccg 20

<210>32

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>32

gctggctttt ccgaataaac 20

<210>33

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>33

gtgaccagca cgaccccagc 20

<210>34

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>34

ccaaagtccc cagggtcacc 20

<210>35

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>35

agttggtccc caaagtcccc 20

<210>36

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>36

gccaaagttg gtccccaaag 20

<210>37

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>37

gtccacacag cggccaaagt 20

<210>38

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>38

ggcaaagagg tccacacagc 20

<210>39

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>39

tggaggcacc aatgatgtcc 20

<210>40

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>40

gctgcagtcg ctggaggcac 20

<210>41

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>41

acaaagcagg tgctgcagtc 20

<210>42

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>42

gcatcatggc tgcaatgcca 20

<210>43

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>43

ggcagacagc atcatggctg 20

<210>44

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>44

gaagtggatc agtctctgcc 20

<210>45

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>45

ttggcagaga agtggatcag 20

<210>46

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>46

catctttggc agagaagtgg 20

<210>47

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>47

tgatgacatc tttggcagag 20

<210>48

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>48

gcctcattga tgacatcttt 20

<210>49

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>49

tcagggaacc aggcctcatt 20

<210>50

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>50

ggtcctcagg gaaccaggcc 20

<210>51

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>51

ggtcagtacc cgctggtcct 20

<210>52

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>52

aaacagctgc caacctgccc 20

<210>53

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>53

ctgcaaaaca gctgccaacc 20

<210>54

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>54

gtaggccccg agtgtgctga 20

<210>55

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>55

agaaactgga gcagctcagc 20

<210>56

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>56

tcctggagaa actggagcag 20

<210>57

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>57

cgttgtgggc ccggcagacc 20

<210>58

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>58

agcaggcagc acctggcaat 20

<210>59

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>59

cacgggtccc catgctggcc 20

<210>60

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>60

ctttgcattc cagacctggg 20

<210>61

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>61

cttgactttg cattccagac 20

<210>62

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>62

ggcagcagat ggcaacggct 20

<210>63

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>63

aaccatttta aagctcagcc 20

<210>64

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>64

tcaagggcca ggccagcagc 20

<210>65

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>65

cccactcaag ggccaggcca 20

<210>66

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>66

atgccccaca gtgagggagg 20

<210>67

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>67

aatggtgaaa tgccccacag 20

<210>68

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>68

catgggaaga atcctgcctc 20

<210>69

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>69

ggagatgagg gccatcagca 20

<210>70

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>70

tagatgccat ccagaaagct 20

<210>71

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>71

tctggctaga tgccatccag 20

<210>72

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>72

ggcatagagc agagtaaagg 20

<210>73

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>73

agcctggcat agagcagagt 20

<210>74

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>74

aagtaagaag aggcttggct 20

<210>75

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>75

gctcaaggag ggacagttgt 20

<210>76

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>76

aaagataaat gtctgcttgc 20

<210>77

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>77

acccaaaaga taaatgtctg 20

<210>78

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>78

tcttcaagtt acaaaagcaa 20

<210>79

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>79

aaatgcaggg ctaaaatcac 20

<210>80

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>80

aacccagttc taatgcacct 20

<210>81

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>81

aagcagggcc tcaggtggaa 20

<210>82

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>82

aaggaaaggg aggcctagag 20

<210>83

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>83

aaggaagact tcaggcaggt 20

<210>84

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>84

aaggtcacac agttaagagt 20

<210>85

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>85

acaaattccc agactcagca 20

<210>86

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>86

acagcattct tggttaggag 20

<210>87

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>87

acccgctggt cctcagggaa 20

<210>88

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>88

actggataca ttggcagaca 20

<210>89

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>89

agaaccatgg agcacctgag 20

<210>90

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>90

agactaggag cctgagtttt 20

<210>91

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>91

agactgatgg aaggcattga 20

<210>92

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>92

agagacagga agctgcagct 20

<210>93

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>93

agagaggagg gcttaaagaa 20

<210>94

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>94

agcatggcac cagcatctgc 20

<210>95

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>95

agctgccaac ctgcaaaaag 20

<210>96

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>96

aggacccaag tcatcctgct 20

<210>97

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>97

agtcaagctg ctgcccagag 20

<210>98

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>98

agtgtaaaat aaagccccta 20

<210>99

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>99

ataaatatct tcaagttaca 20

<210>100

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>100

atctcaggac aggtgagcaa 20

<210>101

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>101

atggctgcaa tgccagccac 20

<210>102

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>102

atgtgcagag atcaatcaca 20

<210>103

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>103

atttcataga caaggaaagg 20

<210>104

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>104

cacagtcctg caaaacagct 20

<210>105

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>105

cacattagcc ttgctcaagt 20

<210>106

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>106

ccagtcagag tagaacagag 20

<210>107

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>107

cccactataa tggcaagccc 20

<210>108

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>108

cccagcccta tcaggaagtg 20

<210>109

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>109

cccctgcaca gagcctggca 20

<210>110

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>110

cctggaaccc ctgcagccag 20

<210>111

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>111

ctagaggaac cactagatat 20

<210>112

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>112

gaagaggctt ggcttcagag 20

<210>113

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>113

gaataacagt gatgtctggc 20

<210>114

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>114

gagaggttca gatccaggcc 20

<210>115

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>115

gagtaaggca ggttactctc 20

<210>116

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>116

gagtagagat tctcatctca 20

<210>117

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>117

gagtcttctg aagtgccatc 20

<210>118

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>118

gcaccatcca gaccagaatc 20

<210>119

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>119

gcagggcggc caccaggttg 20

<210>120

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>120

gctagttatt aagcacctgc 20

<210>121

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>121

ggagcctaca tgtgcagaga 20

<210>122

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>122

ggagggagct tcctggcacc 20

<210>123

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>123

ggcactgccc ttccaccaaa 20

<210>124

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>124

ggccatcagc tggcaatgct 20

<210>125

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>125

ggcctgcaga agccagagag 20

<210>126

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>126

ggtgcataag gagaaagaga 20

<210>127

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>127

ggtggtaatt tgtcacagca 20

<210>128

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>128

gtccccaaag tccccagggt 20

<210>129

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>129

gtgccatctg aacagcacct 20

<210>130

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>130

gtgctgacca cacagtcctg 20

<210>131

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>131

gtgttgagca gactgatgga 20

<210>132

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>132

taaaagctgc aagagactca 20

<210>133

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>133

tagacaagga aagggaggcc 20

<210>134

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>134

tagatgtgac taacatttaa 20

<210>135

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>135

tagcacagcc tggcatagag 20

<210>136

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>136

taggagaaag tagggagagc 20

<210>137

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>137

tagggagagc tcacagatgc 20

<210>138

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>138

tcacagctca ccgagtctgc 20

<210>139

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>139

tcagagaaaa cagtcaccga 20

<210>140

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>140

tcagccaggc caaaggaaga 20

<210>141

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>141

tcatggctgc aatgcctggt 20

<210>142

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>142

tcattttaga gacaggaagc 20

<210>143

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>143

tgaaaatcca tccagcactg 20

<210>144

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>144

tgacatccag gagggaggag 20

<210>145

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>145

tgacatcttg tctgggagcc 20

<210>146

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>146

tgacatttgt gggagaggag 20

<210>147

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>147

tgagttcatt taagagtgga 20

<210>148

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>148

tggcagcaac tcagacatat 20

<210>149

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>149

tgggcattgg tggccccaac 20

<210>150

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>150

tgtgagctct ggcccagtgg 20

<210>151

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>151

tgtgatgacc tggaaaggtg 20

<210>152

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>152

ttcaggcagg ttgctgctag 20

<210>153

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>153

ttgggagcag ctggcagcac 20

<210>154

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>154

ttttaaagct cagccccagc 20

<210>155

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>155

cttatagtta acacacagaa 20

<210>156

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>156

aagtcaacct tatagttaac 20

<210>157

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>157

aggaacaaag ccaaggtcac 20

<210>158

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>158

gtggtgactt accagccacg 20

<210>159

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>159

gcctggagct gacggtgccc 20

<210>160

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>160

gaccgcctgg agctgacggt 20

<210>161

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>161

tccaaggtga catttgtggg 20

<210>162

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>162

aaggctagca ccagctcctc 20

<210>163

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>163

caaggctagc accagctcct 20

<210>164

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>164

gcaaggctag caccagctcc 20

<210>165

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>165

cgcaaggcta gcaccagctc 20

<210>166

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>166

aacgcaaggc tagcaccagc 20

<210>167

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>167

gaacgcaagg ctagcaccag 20

<210>168

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>168

ggaacgcaag gctagcacca 20

<210>169

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>169

cggaacgcaa ggctagcacc 20

<210>170

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>170

tcctcctcgg aacgcaaggc 20

<210>171

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>171

gtgctcgggt gcttcggcca 20

<210>172

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>172

tggaaggtgg ctgtggttcc 20

<210>173

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>173

atccttggcg cagcggtgga 20

<210>174

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>174

ggatccttgg cgcagcggtg 20

<210>175

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>175

ccacggatcc ttggcgcagc 20

<210>176

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>176

cgtaggtgcc aggcaacctc 20

<210>177

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>177

tgactgcgag aggtgggtct 20

<210>178

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>178

cagtgcgctc tgactgcgag 20

<210>179

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>179

ggcagtgcgc tctgactgcg 20

<210>180

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>180

cgggcagtgc gctctgactg 20

<210>181

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>181

cggcgggcag tgcgctctga 20

<210>182

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>182

atccccggcg ggcagcctgg 20

<210>183

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>183

aggtatcccc ggcgggcagc 20

<210>184

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>184

tgaggtatcc ccggcgggca 20

<210>185

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>185

gtgaggtatc cccggcgggc 20

<210>186

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>186

ggtgaggtat ccccggcggg 20

<210>187

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>187

ttggtgaggt atccccggcg 20

<210>188

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>188

cttggtgagg tatccccggc 20

<210>189

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>189

tcttggtgag gtatccccgg 20

<210>190

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>190

atcttggtga ggtatccccg 20

<210>191

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>191

gatcttggtg aggtatcccc 20

<210>192

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>192

aggatcttgg tgaggtatcc 20

<210>193

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>193

gcaggatctt ggtgaggtat 20

<210>194

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>194

atgcaggatc ttggtgaggt 20

<210>195

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>195

acatgcagga tcttggtgag 20

<210>196

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>196

gaagacatgc aggatcttgg 20

<210>197

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>197

agaaggccat ggaagacatg 20

<210>198

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>198

gaagccagga agaaggccat 20

<210>199

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>199

tcttcaccag gaagccagga 20

<210>200

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>200

actcatcttc accaggaagc 20

<210>201

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>201

ccactcatct tcaccaggaa 20

<210>202

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>202

cgccactcat cttcaccagg 20

<210>203

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>203

gtcgccactc atcttcacca 20

<210>204

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>204

aggtcgccac tcatcttcac 20

<210>205

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>205

gcaggtcgcc actcatcttc 20

<210>206

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>206

cagcaggtcg ccactcatct 20

<210>207

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>207

tccagcaggt cgccactcat 20

<210>208

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>208

ggcaacttca aggccagctc 20

<210>209

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>209

gcaaagacag aggagtcctc 20

<210>210

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>210

ttcatccgcc cggtaccgtg 20

<210>211

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>211

tattcatccg cccggtaccg 20

<210>212

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>212

tggtattcat ccgcccggta 20

<210>213

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>213

gctggtattc atccgcccgg 20

<210>214

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>214

gggctggtat tcatccgccc 20

<210>215

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>215

atacacctcc accaggctgc 20

<210>216

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>216

gtgtctagga gatacacctc 20

<210>217

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>217

tgctggtgtc taggagatac 20

<210>218

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>218

tcgatttccc ggtggtcact 20

<210>219

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>219

ctcgatttcc cggtggtcac 20

<210>220

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>220

cctcgatttc ccggtggtca 20

<210>221

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>221

ccctcgattt cccggtggtc 20

<210>222

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>222

tgccctcgat ttcccggtgg 20

<210>223

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>223

ctgccctcga tttcccggtg 20

<210>224

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>224

cctgccctcg atttcccggt 20

<210>225

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>225

ccctgccctc gatttcccgg 20

<210>226

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>226

atgaccctgc cctcgatttc 20

<210>227

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>227

ccatgaccct gccctcgatt 20

<210>228

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>228

gaccatgacc ctgccctcga 20

<210>229

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>229

cggtgaccat gaccctgccc 20

<210>230

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>230

gtcggtgacc atgaccctgc 20

<210>231

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>231

aagtcggtga ccatgaccct 20

<210>232

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>232

cgaagtcggt gaccatgacc 20

<210>233

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>233

ggcacattct cgaagtcggt 20

<210>234

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>234

tggcctgtct gtggaagcgg 20

<210>235

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>235

ggtgggtgcc atgactgtca 20

<210>236

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>236

ccaggtgggt gccatgactg 20

<210>237

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>237

cctgccaggt gggtgccatg 20

<210>238

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>238

ccacccctgc caggtgggtg 20

<210>239

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>239

gctgaccacc cctgccaggt 20

<210>240

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>240

tcccggccgc tgaccacccc 20

<210>241

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>241

ggcatcccgg ccgctgacca 20

<210>242

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>242

gccggcatcc cggccgctga 20

<210>243

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>243

gccacgccgg catcccggcc 20

<210>244

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>244

ggccacgccg gcatcccggc 20

<210>245

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>245

tggccacgcc ggcatcccgg 20

<210>246

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>246

ttggccacgc cggcatcccg 20

<210>247

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>247

cttggccacg ccggcatccc 20

<210>248

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>248

ccttggccac gccggcatcc 20

<210>249

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>249

cccttggcca cgccggcatc 20

<210>250

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>250

cacccttggc cacgccggca 20

<210>251

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>251

gcacccttgg ccacgccggc 20

<210>252

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>252

ggcacccttg gccacgccgg 20

<210>253

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>253

tggcaccctt ggccacgccg 20

<210>254

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>254

ctggcaccct tggccacgcc 20

<210>255

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>255

gctggcaccc ttggccacgc 20

<210>256

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>256

cgcatgctgg cacccttggc 20

<210>257

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>257

cagttgagca cgcgcaggct 20

<210>258

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>258

ggcagttgag cacgcgcagg 20

<210>259

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>259

ccttggcagt tgagcacgcg 20

<210>260

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>260

ccttcccttg gcagttgagc 20

<210>261

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>261

gtgcccttcc cttggcagtt 20

<210>262

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>262

ccgtgccctt cccttggcag 20

<210>263

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>263

ggtgccgcta accgtgccct 20

<210>264

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>264

caggcctatg agggtgccgc 20

<210>265

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>265

ccgaataaac tccaggccta 20

<210>266

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>266

tggcttttcc gaataaactc 20

<210>267

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>267

cagctggctt ttccgaataa 20

<210>268

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>268

accagctggc ttttccgaat 20

<210>269

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>269

ggaccagctg gcttttccga 20

<210>270

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>270

ggctggacca gctggctttt 20

<210>271

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>271

gtggccccac aggctggacc 20

<210>272

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>272

agcagcacca ccagtggccc 20

<210>273

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>273

gctgtaccca cccgccaggg 20

<210>274

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>274

cgaccccagc cctcgccagg 20

<210>275

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>275

cggtgaccag cacgacccca 20

<210>276

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>276

agcggtgacc agcacgaccc 20

<210>277

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>277

gcagcggtga ccagcacgac 20

<210>278

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>278

cggcagcggt gaccagcacg 20

<210>279

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>279

ccggcagcgg tgaccagcac 20

<210>280

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>280

ttgccggcag cggtgaccag 20

<210>281

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>281

agttgccggc agcggtgacc 20

<210>282

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>282

gaagttgccg gcagcggtga 20

<210>283

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>283

cggaagttgc cggcagcggt 20

<210>284

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>284

cccggaagtt gccggcagcg 20

<210>285

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>285

gtcccggaag ttgccggcag 20

<210>286

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>286

atgacctcgg gagctgaggc 20

<210>287

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>287

cccaactgtg atgacctcgg 20

<210>288

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>288

ggcattggtg gccccaactg 20

<210>289

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>289

gctggtcttg ggcattggtg 20

<210>290

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>290

cccagggtca ccggctggtc 20

<210>291

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>291

tccccagggt caccggctgg 20

<210>292

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>292

agtccccagg gtcaccggct 20

<210>293

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>293

aaagtcccca gggtcaccgg 20

<210>294

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>294

ccccaaagtc cccagggtca 20

<210>295

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>295

ttggtcccca aagtccccag 20

<210>296

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>296

aaagttggtc cccaaagtcc 20

<210>297

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>297

cggccaaagt tggtccccaa 20

<210>298

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>298

agcggccaaa gttggtcccc 20

<210>299

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>299

acagcggcca aagttggtcc 20

<210>300

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>300

acacagcggc caaagttggt 20

<210>301

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>301

ccacacagcg gccaaagttg 20

<210>302

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>302

aggtccacac agcggccaaa 20

<210>303

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>303

agaggtccac acagcggcca 20

<210>304

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>304

aaagaggtcc acacagcggc 20

<210>305

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>305

caatgatgtc ctcccctggg 20

<210>306

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>306

gaggcaccaa tgatgtcctc 20

<210>307

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>307

gctggaggca ccaatgatgt 20

<210>308

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>308

tcgctggagg caccaatgat 20

<210>309

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>309

agtcgctgga ggcaccaatg 20

<210>310

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>310

gcagtcgctg gaggcaccaa 20

<210>311

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>311

gtgctgcagt cgctggaggc 20

<210>312

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>312

aggtgctgca gtcgctggag 20

<210>313

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>313

gcaggtgctg cagtcgctgg 20

<210>314

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>314

agcaggtgct gcagtcgctg 20

<210>315

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>315

aaagcaggtg ctgcagtcgc 20

<210>316

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>316

acacaaagca ggtgctgcag 20

<210>317

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>317

tgacacaaag caggtgctgc 20

<210>318

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>318

tcccactctg tgacacaaag 20

<210>319

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>319

tcatggctgc aatgccagcc 20

<210>320

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>320

cagcatcatg gctgcaatgc 20

<210>321

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>321

gacagcatca tggctgcaat 20

<210>322

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>322

cagacagcat catggctgca 20

<210>323

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>323

tcggcagaca gcatcatggc 20

<210>324

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>324

gctcggcaga cagcatcatg 20

<210>325

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>325

cggctcggca gacagcatca 20

<210>326

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>326

tccggctcgg cagacagcat 20

<210>327

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>327

cggccagggt gagctccggc 20

<210>328

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>328

ctctgcctca actcggccag 20

<210>329

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>329

gtctctgcct caactcggcc 20

<210>330

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>330

cagtctctgc ctcaactcgg 20

<210>331

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>331

atcagtctct gcctcaactc 20

<210>332

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>332

ggatcagtct ctgcctcaac 20

<210>333

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>333

gtggatcagt ctctgcctca 20

<210>334

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>334

aagtggatca gtctctgcct 20

<210>335

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>335

gagaagtgga tcagtctctg 20

<210>336

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>336

cagagaagtg gatcagtctc 20

<210>337

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>337

ggcagagaag tggatcagtc 20

<210>338

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>338

ctttggcaga gaagtggatc 20

<210>339

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>339

gacatctttg gcagagaagt 20

<210>340

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>340

atgacatctt tggcagagaa 20

<210>341

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>341

attgatgaca tctttggcag 20

<210>342

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>342

tcattgatga catctttggc 20

<210>343

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>343

aggcctcatt gatgacatct 20

<210>344

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>344

ccaggcctca ttgatgacat 20

<210>345

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>345

aaccaggcct cattgatgac 20

<210>346

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>346

ggaaccaggc ctcattgatg 20

<210>347

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>347

gggaaccagg cctcattgat 20

<210>348

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>348

agggaaccag gcctcattga 20

<210>349

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>349

cagggaacca ggcctcattg 20

<210>350

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>350

ctcagggaac caggcctcat 20

<210>351

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>351

cctcagggaa ccaggcctca 20

<210>352

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>352

tcctcaggga accaggcctc 20

<210>353

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>353

gtcctcaggg aaccaggcct 20

<210>354

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>354

tggtcctcag ggaaccaggc 20

<210>355

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>355

ctggtcctca gggaaccagg 20

<210>356

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>356

gctggtcctc agggaaccag 20

<210>357

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>357

cgctggtcct cagggaacca 20

<210>358

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>358

gtacccgctg gtcctcaggg 20

<210>359

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>359

cagtacccgc tggtcctcag 20

<210>360

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>360

acctgcccca tgggtgctgg 20

<210>361

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>361

caaaacagct gccaacctgc 20

<210>362

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>362

tcctgcaaaa cagctgccaa 20

<210>363

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>363

agtcctgcaa aacagctgcc 20

<210>364

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>364

gctgaccata cagtcctgca 20

<210>365

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>365

ggccccgagt gtgctgacca 20

<210>366

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>366

gtgtaggccc cgagtgtgct 20

<210>367

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>367

ccgtgtaggc cccgagtgtg 20

<210>368

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>368

atccgtgtag gccccgagtg 20

<210>369

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>369

ccatccgtgt aggccccgag 20

<210>370

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>370

ggccatccgt gtaggccccg 20

<210>371

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>371

gtggccatcc gtgtaggccc 20

<210>372

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>372

ctggagcagc tcagcagctc 20

<210>373

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>373

aactggagca gctcagcagc 20

<210>374

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>374

ggagaaactg gagcagctca 20

<210>375

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>375

ctggagaaac tggagcagct 20

<210>376

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>376

cacctggcaa tggcgtagac 20

<210>377

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>377

gcacctggca atggcgtaga 20

<210>378

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>378

agcacctggc aatggcgtag 20

<210>379

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>379

cagcacctgg caatggcgta 20

<210>380

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>380

gcagcacctg gcaatggcgt 20

<210>381

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>381

ggcagcacct ggcaatggcg 20

<210>382

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>382

aggcagcacc tggcaatggc 20

<210>383

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>383

caggcagcac ctggcaatgg 20

<210>384

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>384

gcaggcagca cctggcaatg 20

<210>385

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>385

tagcaggcag cacctggcaa 20

<210>386

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>386

gtagcaggca gcacctggca 20

<210>387

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>387

tggcctcagc tggtggagct 20

<210>388

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>388

gtccccatgc tggcctcagc 20

<210>389

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>389

ggtccccatg ctggcctcag 20

<210>390

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>390

gggtccccat gctggcctca 20

<210>391

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>391

cgggtcccca tgctggcctc 20

<210>392

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>392

acgggtcccc atgctggcct 20

<210>393

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>393

acacgggtcc ccatgctggc 20

<210>394

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>394

gacacgggtc cccatgctgg 20

<210>395

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>395

ggacacgggt ccccatgctg 20

<210>396

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>396

tggacacggg tccccatgct 20

<210>397

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>397

gtggacacgg gtccccatgc 20

<210>398

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>398

agtggacacg ggtccccatg 20

<210>399

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>399

cagtggacac gggtccccat 20

<210>400

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>400

gcagtggaca cgggtcccca 20

<210>401

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>401

ggcagtggac acgggtcccc 20

<210>402

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>402

tggcagtgga cacgggtccc 20

<210>403

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>403

gtggcagtgg acacgggtcc 20

<210>404

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>404

ggtggcagtg gacacgggtc 20

<210>405

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>405

tggtggcagt ggacacgggt 20

<210>406

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>406

tgttggtggc agtggacacg 20

<210>407

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>407

agctgcagcc tgtgaggacg 20

<210>408

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>408

gtgccaaggt cctccacctc 20

<210>409

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>409

tcagcacagg cggcttgtgg 20

<210>410

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>410

ccacgcactg gttgggctga 20

<210>411

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>411

actttgcatt ccagacctgg 20

<210>412

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>412

gactttgcat tccagacctg 20

<210>413

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>413

tgactttgca ttccagacct 20

<210>414

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>414

ttgactttgc attccagacc 20

<210>415

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>415

tccttgactt tgcattccag 20

<210>416

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>416

cgggattcca tgctccttga 20

<210>417

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>417

gcaggccacg gtcacctgct 20

<210>418

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>418

ggagggcact gcagccagtc 20

<210>419

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>419

cagatggcaa cggctgtcac 20

<210>420

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>420

gcagatggca acggctgtca 20

<210>421

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>421

agcagatggc aacggctgtc 20

<210>422

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>422

cagcagatgg caacggctgt 20

<210>423

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>423

gcagcagatg gcaacggctg 20

<210>424

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>424

cggcagcaga tggcaacggc 20

<210>425

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>425

ccggcagcag atggcaacgg 20

<210>426

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>426

tccggcagca gatggcaacg 20

<210>427

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>427

ctccggcagc agatggcaac 20

<210>428

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>428

gctccggcag cagatggcaa 20

<210>429

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>429

ccaggtgccg gctccggcag 20

<210>430

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>430

gaggcctgcg ccaggtgccg 20

<210>431

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>431

atgagggcca tcagcacctt 20

<210>432

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>432

gatgagggcc atcagcacct 20

<210>433

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>433

agatgagggc catcagcacc 20

<210>434

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>434

gagatgaggg ccatcagcac 20

<210>435

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>435

tggagatgag ggccatcagc 20

<210>436

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>436

ctggagatga gggccatcag 20

<210>437

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>437

gctggagatg agggccatca 20

<210>438

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>438

agctggagat gagggccatc 20

<210>439

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>439

gctagatgcc atccagaaag 20

<210>440

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>440

ggctagatgc catccagaaa 20

<210>441

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>441

tggctagatg ccatccagaa 20

<210>442

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>442

ctggctagat gccatccaga 20

<210>443

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>443

ctctggctag atgccatcca 20

<210>444

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>444

cctctggcta gatgccatcc 20

<210>445

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>445

gcctctggct agatgccatc 20

<210>446

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>446

agcctctggc tagatgccat 20

<210>447

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>447

acccttggtc acgccggcat 20

<210>448

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>448

ctgcccttcc accaaaatgc 20

<210>449

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>449

actgcccttc caccaaaatg 20

<210>450

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>450

cactgccctt ccaccaaaat 20

<210>451

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>451

gcactgccct tccaccaaaa 20

<210>452

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>452

gggcactgcc cttccaccaa 20

<210>453

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>453

tgggcactgc ccttccacca 20

<210>454

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>454

ctgggcactg cccttccacc 20

<210>455

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>455

gctgggcact gcccttccac 20

<210>456

<211>19

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>456

gagcaacttc ggaggcagc 19

<210>457

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>457

gcctcagtct gcttcgcacc 20

<210>458

<211>14

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>458

gcctatgagg gtgc 14

<210>459

<211>14

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>459

tccaggccta tgag 14

<210>460

<211>14

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>460

cagctcagca gctc 14

<210>461

<211>14

<212>DNA

＜213〉artificial sequence

<220>

＜223〉synthetic oligonucleotide

<400>461

ttaatcaggg agcc 14

Claims (281)

1. A compound comprising a modified oligonucleotide, which is composed of 12-30 connected nucleosides and has the following nucleobase sequence, said nucleobase sequence comprising and following Components consisting of at least 8 consecutive nucleobases complementary to each other in equal length: SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735 -1765, 1740-1765, 1849-1876, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943 , 1917-1944, 1918-1945, 1919-1946, 1920-1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928 -1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334 , 2310-2334, 2410-2434, 2504-2528, 2509-2528, 2582-2625, 2606-2668, 2828-2855, 2832-2851, 2900-2927, 2900-2929, 2902-2927, 2983-3007, 2983 -3013, 3227-3252, 3227-3456, 3472-3496 or 3543-3569 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 2. The compound of claim 1, wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1. 3. The compound of claim 2, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 4. The compound of claim 1, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-18 76, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 5. The compound of claim 2, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-18 76, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 6. The compound of claim 3, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-18 76, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 7. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having a nucleobase sequence comprising the following part, which is the same as At least 8 consecutive nucleobases that are fully complementary to the long portion: the nucleobase of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 167 2-1698,1681-1706,1735-1761,1735-1765,1740-1765,1849-1876,1849-1879,1850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854- 1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946, 1920-1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306- 2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528, 2509-2528, 2582-2625, 2606-2668, 2828-2855, 2832-2851, 2900-2927, 2900-2929, 2902-2927, 2983-3007, 2983-3013, 3227-3252, 3227-3456, 3472-3496 or 3543-3569 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 8. The compound of claim 7, wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1. 9. The compound of claim 7, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:1. 10. The compound of claim 7, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 60O- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-547, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-18 76, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 11. The compound of claim 8, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600-639, 600-670, 601-528, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835- 859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960-1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998- 1025, 999-1026, 1000-1027, 1001-1028, 1002-1029, 1003-1029, 1004-1029, 1005-1029, 1006-1029, 1007-1034, 1036-1061, 1045-1072, 1076-1096, 1088-1115,1098-1123,1200-1251,1210-1237,1219-1245,1228-1251,1273-1444,1295-1316,1318-1345,1328-1354,1337-1361,1344-1371,1354- 1377, 1380-1406, 1389-1416, 1400-1426, 1409-1434, 1465-1491, 1465-1602, 1474-1499, 1482-1519, 1513-1540, 1523-1549, 1526-1602, 1526-1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628- 1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-187 6, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 12. The compound of claim 9, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-18 76, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946,1920-1939,1920-1947,1921-1948,1922-1949,1923-1950,1924-1951,1925-1952,1926-1952,1927-1952,1928-1955,1962-2059,2040- 2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528,2509-2528,2582-2625,2606-2668,2828-2855,2832-2851,2900-2927,2900-2929,2902-2927,2983-3007,2983-3013,3227-3252,3227- 3456, 3472-3496 or 3543-3569 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 13. The compound of claim 1 consisting of a single stranded modified oligonucleotide. 14. The compound of claim 13, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 15. The compound of claim 1, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 16. The compound of claim 15, wherein at least one nucleoside comprises a modified sugar. 17. The compound of claim 16, wherein at least one modified sugar is a bicyclic sugar. 18. The compound of claim 17, wherein at least one modified sugar comprises a 2'-O-methoxyethyl group. 19. The compound of claim 15, wherein at least one nucleoside comprises a modified nucleobase. 20. The compound of claim 19, wherein the modified nucleobase is 5-methylcytosine. 21. The compound of claim 1, wherein said modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a linking 3' wing segment consisting of nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment; and wherein each nucleoside of each wing segment comprises Modified sugars. 22. The compound of claim 21, wherein said modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of 5 linked nucleosides; and a 3' wing segment consisting of 5 linked nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment, wherein each of each wing segment Each nucleoside contains a 2'-O-methoxyethyl sugar; and each internucleoside linkage is a phosphorothioate linkage. 23. The antisense compound of claim 21, wherein the antisense compound is a chimeric oligonucleotide consisting of: a gap segment consisting of 10-18 linked 2'-deoxynucleosides; A 5' wing segment consisting of 1-5 linked nucleosides; and a 3' wing segment consisting of 1-5 linked nucleosides; wherein each nucleoside of the 5' wing segment is is a sugar-modified nucleoside, each nucleoside of the 3' wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 24. The compound of claim 2, wherein said modified oligonucleotide consists of 20 linked nucleosides. 25. A composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and a nucleobase as follows, or a salt thereof and a pharmaceutically acceptable carrier or diluent base sequence, the nucleobase sequence comprising at least 8 consecutive nucleobases selected from the nucleobase sequence of the following group: SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 1 850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854-1879,1905-1955,1915-1942,1916-1943,1917-1944,1918-1945,1919-1946,1920- 1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509- and 3543-3569 Nucleobase sequence shown. 26. The composition of claim 25, wherein the modified oligonucleotide is a single stranded oligonucleotide. 27. The composition of claim 25, wherein said modified oligonucleotide consists of 20 linked nucleosides. 28. A method comprising administering to an animal a modified oligonucleotide consisting of 12-30 linked nucleosides and having a nucleobase sequence comprising a part, said part Consists of at least 8 contiguous nucleobases complementary to the isometric portion of: SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 1 850-1877,1851-1877,1852-1878,1852-1879,1853-1879,1854-1879,1905-1955,1915-1942,1916-1943,1917-1944,1918-1945,1919-1946,1920- 1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509- or 3543-3569 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:1. 29. The method of claim 28, wherein said animal is a human. 30. The method of claim 29, wherein administration of said compound slows progression and/or ameliorate hypercholesterolemia, acute coronary syndrome, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, premature coronary heart disease , type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improved cardiovascular outcome, or any combination thereof. 31. The method of claim 28, comprising co-administering said compound and at least one additional therapy. 32. The method of claim 31, wherein said compound and an additional therapy are administered concomitantly. 33. The method of claim 31, wherein the compound and the additional therapy are administered in the same formulation. 34. The method of claim 31, wherein said additional therapy is a lipid-lowering therapy. 35. The method of claim 34, wherein the lipid-lowering therapy is a therapeutic lifestyle modification, an HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an MTP inhibitor, an antisense compound targeting ApoB, or any combination thereof . 36. The method of claim 35, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin. 37. The method of claim 35, wherein the cholesterol absorption inhibitor is ezetimibe. 38. The method of claim 35, wherein said additional lipid-lowering therapy comprises an HMG-CoA reductase inhibitor and a cholesterol absorption inhibitor, said HMG-CoA reductase inhibitor being simvastatin, said cholesterol dilution inhibitor It's ezetimibe. 39. The method of claim 35, wherein the antisense compound is ISIS 301012. 40. The method of claim 28, wherein said administering is parenteral. 41. The method of claim 40, wherein said parenteral administration comprises subcutaneous or intravenous administration. 42. The method of claim 28, wherein said administering comprises oral administration. 43. A method comprising administering to patients with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, premature coronary heart disease, type II diabetes, accompanied by blood lipid Disorders of type II diabetes, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, A human with elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol is administered a therapeutically effective amount of a composition comprising a modified oligonucleotide The acid is composed of 12-30 connected nucleosides and has the following nucleobase sequence, which comprises at least 8 consecutive nucleobases complementary to the following equal-length parts: SEQ ID NO: 1 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600- 639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960- 1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025,999-1026,1000-1027,1001-1028,1002-1029,1003-1029,1004-1029,1005-1029,1006-1029,1007-1034,1036-1061,1045-1072,1076- 1096, 1088-115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377,1380-1406,1389-1416,1400-1426,1409-1434,1465-1491,1465-1602,1474-1499,1482-1519,1513-1540,1523-1549,1526-1602,1526- 1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 18 50-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946, 1920- 1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139,2100-2206,2101-2126,2305-2332,2305-2354,2306-2333,2307-2334,2308-2334,2309-2334,2310-2334,2410-2434,2504-2528,2509- or 3543-3569 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1. 44. The method of claim 28, wherein the animal suffers from hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, acute coronary syndrome, premature coronary heart disease, One or more risk factors for coronary heart disease, type 2 diabetes, type 2 diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, high Fatty acidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated IDL-cholesterol, or elevated non-HDL cholesterol . 45. The method of claim 44, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL. 46. The method of claim 44, wherein administering said compound to said animal reduces LDL-cholesterol levels. 47. The method of claim 46, wherein administering the compound results in LDL-cholesterol levels below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, or 50 mg/dL. 48. The method of claim 44, wherein the one or more risk factors are selected from age, smoking, high blood pressure, low HDL-cholesterol, and family history of early coronary heart disease. 49. The method of claim 44, wherein the animal fails to achieve LDL-cholesterol target levels following lipid-lowering therapy, fails to comply with recommended therapy, develops treatment side effects, or any combination thereof. 50. The method of claim 49, wherein the lipid-lowering therapy is a statin. 51. The method of claim 49, wherein the lipid-lowering therapy is ezetimibe. 52. The method of claim 28, wherein administering results in ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particles, small VLDL-particles, non-HDL-cholesterol, liver triglyceride levels, serum glycerol A reduction in triglycerides, serum phospholipids, or any combination thereof. 53. The method of claim 52, wherein said ApoB reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, At least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 54. The method of claim 53, wherein the reduction in ApoB is between 10% and 80%, between 20% and 70%, between 30% and 60%, or between 30% and 70%. 55. The method of claim 52, wherein said LDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 56. The method of claim 52, wherein said lower VLDL-cholesterol is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 57. The method of claim 52, wherein said Lp(a) reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 58. The method of claim 52, wherein said small LDL-particle reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 59. The method of claim 52, wherein the small VLDL-particle reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 60. The method of claim 52, wherein said non-HDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 61. The method of claim 52, wherein the reduction in hepatic triglyceride levels is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% , at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 62. The method of claim 52, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum triglycerides. 63. The method of claim 52, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum phospholipids. 64. The method of claim 52 or 53, wherein the serum phospholipid is a serum oxidized phospholipid. 65. The method of claim 28, wherein administering results in a reduction in the risk of coronary heart disease, or slowing, stopping or preventing progression of atherosclerosis, or any combination thereof. 66. The method of claim 28, wherein administering results in improved cardiovascular outcome in the human. 67. The method of claim 66, wherein the improved cardiovascular outcome is improved carotid intima-media thickness, improved atheroma thickness, increased HDL-cholesterol, or any combination thereof. 68. The method of claim 28, wherein administering improves hepatic steatosis, resulting in lowered lipids, improved LDL/HDL ratio, or any combination thereof. 69. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having a nucleobase sequence comprising a part consisting of The long portion is complementary to at least 8 consecutive nucleobases: SEQ ID NO: 2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15264-15290, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 153297 23, 15298-15323, 15299-15323, 15300-15323, 15301-15328, 15330-15355, 15330-15490, 15339-15366, 15358-15490, 16134-16153, 16668, 16671-172, 272 18561-18580，18591-18618，18591-18646，18591-18668，18695-18746，18705-18730，18709-18736，18719-18746，19203-20080，19931-19952，19954-19981，19964-19990，19973- 19999, 19982-20009, 119992-20016, 20016-20042, 20025-20052, 20036-20062, 20045-20070, 20100-20119, 20188-20207, 20624-20650, 20629-20804, 20633-26666666666666666666666666666666666666666666666666666666666666 20635-20781, 20657-2067676, 20680697, 20680-20706, 20683-20781, 20689-20715, 20698-20736, 20709-20718718718-2078-20717-207187336, 20709-20717-207336, 20717-8744. 20747，20721-20748，20722-20749，20727-20752，20735-20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209， 21181-21211, 21183-21211, 21481-21500, 21692-21719, 2222227, 22096-22222233, 22096-2222233, 22133-22131313134, 2213134, 2213134, 221313, 22134, 22131313. 22162, 22136-22163, 22137-22163, 22138-22163, 22189-22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 2 2202-22229，22203-22230，22204-22231，22205-22232，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292- 22311，23985-24054，24035-24134，24095-24121，24858-24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141， 26115-26141，26116-26141，26117-26141，26117-26475，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635- 26662, 26707-26734, 26707-26736, 26790-26820, 27034-27263, 27279-27303 or 27350-27376 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 70. The compound of claim 69, wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO:2. 71. The compound of claim 70, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:2. 72. The compound of claim 69, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 73. The compound of claim 70, wherein said modified oligonucleotide is specifically at the position of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 2. 74. The compound of claim 71, wherein said modified oligonucleotide is specifically at the position of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 2219-222227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 75. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having a nucleobase sequence comprising the following part, which is the same as At least 8 consecutive nucleobases of complete complementarity in the long part: SEQ ID NO: 2 nucleobases 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15264-15290, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 1529 7-15323, 15298-15323, 15299-15323, 15300-15323, 15301-15328, 15330-15355, 15330-15490, 15339-15366, 15358-15490, 16134-16153, 16768-1867 18427, 18561-1880, 18591-18618, 18591-18646, 18591-18668, 18695-18746, 18705-18730, 18709-18736, 18719-18746, 19203-20080, 199931-199952, 199999999999999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 19973-19999, 1999-20009, 19992-20016, 20016-20042, 20025-20052, 20036-20062, 20045-20070, 20100-20119, 20188-20207 ,20624-20650, 20629-20804, 206293333333333333333333333333333333333333333333333333333333333333333 20660，20635-20781，20643-20662，20657-20676，20670-20697，20680-20706，20683-20781，20689-20715，20698-20725，20709-20736，20717-20744，20718-20745，20719-20746， 20721-20748, 20722-20749, 20727-20752, 20735-20759, 20762-21014, 20782-21014, 21082-211114, 2118-2111114, 21082-211152 21209, 21181-21211, 21183-21211, 21481-21500, 21589-21608, 21692-21719, 22000-22227, 22096-22115, 22096-222233, 22133-221632163, 22163-2216321632163. 22135-22162, 22136-22163, 22137-22163, 22138-22163, 22189-22239, 22199-22226, 22199-22227, 22200-22227, 22201-22 228, 22202-222299, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234, 22208-22235, 22209-22236, 22222223333333333333333333333333333333333333333333333333333333. 22292-22311，23985-24054，24035-24134，24095-24121，24858-24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114- 26141，26115-26141，26116-26141，26117-26141，26117-26475，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576， 26635-26662, 26707-26734, 26707-26736, 26790-26820, 27034-27263, 27279-27303 or 27350-27376 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 76. The compound of claim 75, wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO:2. 77. The compound of claim 75, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:2. 78. The compound of claim 75, wherein said modified oligonucleotide is specifically at the position of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 79. The compound of claim 76, wherein said modified oligonucleotide is specifically at the position of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 152999999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 80. The compound of claim 77, wherein said modified oligonucleotide is specifically at the end of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-5563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-1 5328，15330-15355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668， 18695-18746, 18705-18730, 18709-18736, 19203-20080, 199931-19952, 19954-19981, 19964-199990, 199982-20009, 11992-20016, 20016-2002525252525252525252525 20052，20036-20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697， 20680-20706, 20689-20715, 20698-20725, 20698-20736, 20709-20744, 20718-20745, 20721-207272727272727272727272747, 2072-2074747, 20721-20748-20748-20748-20748-20748-20748-20748-2072727. 20759，20762-21014，20785-21014，21082-21107，21082-21152，21091-21114，21118-21144，21127-21152，21181-21209，21181-21211，21183-21211，21481-21500，21589-21608， 21692-21719, 2222227, 22096-222233, 22096-22311, 22133-22163, 22134-22161, 22131313131313131313131313131313162 22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232 ，22206-22233，22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858 -24877，24907-24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475 ，26118-26141，26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034 -27263, 27279-27303 or 27350-27376 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 81. The compound of claim 69 consisting of a single stranded modified oligonucleotide. 82. The compound of claim 81, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 83. The compound of claim 69, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 84. The compound of claim 83, wherein at least one nucleoside comprises a modified sugar. 85. The compound of claim 84, wherein at least one modified sugar is a bicyclic sugar. 86. The compound of claim 85, wherein at least one modified sugar comprises a 2'-O-methoxyethyl group. 87. The compound of claim 83, wherein at least one nucleoside comprises a modified nucleobase. 88. The compound of claim 87, wherein the modified nucleobase is 5-methylcytosine. 89. The compound of claim 69, wherein said modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a linking 3' wing segment consisting of nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment; and wherein each nucleoside of each wing segment comprises Modified sugars. 90. The compound of claim 89, wherein said modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of 5 linked nucleosides; and a 3' wing segment consisting of 5 linked nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment, wherein each of each wing segment Each nucleoside contains a 2'-O-methoxyethyl sugar; and each internucleoside linkage is a phosphorothioate linkage. 91. The antisense compound of claim 89, wherein the antisense compound is a chimeric oligonucleotide consisting of: a gap segment consisting of 10-18 linked 2'-deoxynucleosides; A 5' wing segment consisting of 1-5 linked nucleosides; and a 3' wing segment consisting of 1-5 linked nucleosides; wherein each nucleoside of the 5' wing segment is is a sugar-modified nucleoside, each nucleoside of the 3' wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 92. The compound of claim 70, wherein said modified oligonucleotide consists of 20 linked nucleosides. 93. A composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and a nucleobase as follows, or a salt thereof and a pharmaceutically acceptable carrier or diluent base sequence, the nucleobase sequence comprises at least 8 consecutive nucleobases selected from the nucleobase sequence of the following group: of SEQ ID NO:2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-15328, 15330-15 355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668，18695-18746， 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-199999, 19982-20009, 19992-20016, 20016-20042, 20025-20052,2003666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666-00366-20052,20052,20036 20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697，20680-20706， 20683-20781, 20698-20725 ,20709-20736, 20709-20744, 20718-20745, 20719-20747, 20722-207273-2075273, 20721-20748, 20721-20748, 20722-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-20752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752. 21014 ,20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 2118183-21211, 214889-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160. 222227, 22096-22115, 22096-222311, 22133-22160, 22132163, 22134-22163, 22136-2213189189189189189189189163, 2213. 22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858-24877，24907- 24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475，26118-26141， 26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034-27263，27279- 27303 and 27350-27376 Nucleobase sequence shown. 94. The composition of claim 93, wherein the modified oligonucleotide is a single stranded oligonucleotide. 95. The composition of claim 93, wherein said modified oligonucleotide consists of 20 linked nucleosides. 96. A method comprising administering to an animal a modified oligonucleotide consisting of 12-30 linked nucleosides and having a nucleobase sequence comprising the following part, said part Consists of at least 8 contiguous nucleobases complementary to the isometric portion of: SEQ ID NO: 2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-15328, 15330-15 355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668，18695-18746， 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-199999, 19982-20009, 19992-20016, 20016-20042, 20025-20052,2003666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666-00366-20052,20052,20036 20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697，20680-20706， 20683-20781, 20698-20725 ,20709-20736, 20709-20744, 20718-20745, 20719-20747, 20722-207273-2075273, 20721-20748, 20721-20748, 20722-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-20752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752. 21014 ,20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 2118183-21211, 214889-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160. 222227, 22096-22115, 22096-222311, 22133-22160, 22132163, 22134-22163, 22136-2213189189189189189189189163, 2213. 22226, 22199-22227, 22200-2222722201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 2 22208-222335, 22209-22236, 22210-22239, 222222336, 222222339, 222292323, 222985-22233, 22285-22233, 24878785. 24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475，26118-26141， 26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034-27263，27279- 27303 or 27350-27376 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 97. The method of claim 96, wherein said animal is a human. 98. The method of claim 97, wherein administration of said compound slows progression and/or improves hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, premature coronary heart disease , type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improved cardiovascular outcome, or any combination thereof. 99. The method of claim 96, comprising co-administering said compound and at least one additional therapy. 100. The method of claim 99, wherein said compound and an additional therapy are administered concomitantly. 101. The method of claim 99, wherein the compound and the additional therapy are administered in the same formulation. 102. The method of claim 99, wherein said additional therapy is lipid-lowering therapy. 103. The method of claim 102, wherein the lipid-lowering therapy is a therapeutic lifestyle change, an HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an MTP inhibitor, an antisense compound targeting ApoB, or any combination thereof . 104. The method of claim 103, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin. 105. The method of claim 103, wherein the cholesterol absorption inhibitor is ezetimibe. 106. The method of claim 103, wherein said additional lipid-lowering therapy comprises an HMG-CoA reductase inhibitor and a cholesterol absorption inhibitor, said HMG-CoA reductase inhibitor is simvastatin, said cholesterol dilution inhibitor It's ezetimibe. 107. The method of claim 103, wherein the antisense compound is ISIS 301012. 108. The method of claim 96, wherein said administering is parenteral. 109. The method of claim 108, wherein said parenteral administration comprises subcutaneous or intravenous administration. 110. The method of claim 96, wherein said administering comprises oral administration. 111. A method comprising administering to patients with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, premature coronary heart disease, type II diabetes, with blood lipid Disorders of type II diabetes, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, A human with elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol is administered a therapeutically effective amount of a composition comprising a modified oligonucleotide The acid is composed of 12-30 connected nucleosides and has the following nucleobase sequence, which comprises at least 8 consecutive nucleobases complementary to the following equal-length parts: SEQ ID NO: 2 2274-2400,2274-2575,2433-2570,2433-2579,2549-2575,2552-2579,2585-2638,2605-2638,3056-3075,4150-5159,4306-4325,5590-5618,5667- 5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 8948- 8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-137947, 13746-13779, 13903-13945, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14601-14650, 146750,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650,14650. 14700, 14675-14777, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14998, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-1528, 15254-15328, 15279-15305, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15298-15323, 15299999999999999999999999999999999999999999999999999999999999999999999999999999999999999999 15323, 15300-15323, 15301-15328, 15330-15 355，15330-15490，15339-15366，15358-15490，16134-16153，16668-16687，17267-17286，18377-18427，18561-18580，18591-18618，18591-18646，18591-18668，18695-18746， 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-199999, 19982-20009, 19992-20016, 20016-20042, 20025-20052,2003666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666-00366-20052,20052,20036 20062，20045-20070，20100-20119，20188-20207，20624-20650，20624-20759，20629-20804，20633-20660，20635-20781，20643-20662，20657-20676，20670-20697，20680-20706， 20683-20781, 20698-20725 ,20709-20736, 20709-20744, 20718-20745, 20719-20747, 20722-207273-2075273, 20721-20748, 20721-20748, 20722-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-2073-20752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752, 2072752. 21014 ,20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 2118183-21211, 214889-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160, 21589-2160. 222227, 22096-22115, 22096-222311, 22133-22160, 22132163, 22134-22163, 22136-2213189189189189189189189163, 2213. 22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234，22208-22235，22209-22236，22210-22236，22210-22239，22211-22236，22212-22239，22292-22311，23985-24054，24035-24134，24095-24121，24858-24877，24907- 24926，25413-25432，25994-26013，26112-26139，26112-26161，26112-27303，26113-26140，26114-26141，26115-26141，26116-26141，26117-26141，26117-26475，26118-26141， 26120-26141，26132-26151，26142-26161，26217-26241，26311-26335，26389-26432，26456-26576，26635-26662，26707-26734，26707-26736，26790-26820，27034-27263，27279- 27303 or 27350-27376 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:2. 112. The method of claim 96, wherein the animal suffers from hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, acute coronary syndrome, premature coronary heart disease, One or more risk factors for coronary heart disease, type 2 diabetes, type 2 diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, high Fatty acidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated IDL-cholesterol, or elevated non-HDL cholesterol . 113. The method of claim 112, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL. 114. The method of claim 112, wherein administering said compound to said animal reduces LDL-cholesterol levels. 115. The method of claim 114, wherein administering the compound results in LDL-cholesterol levels below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, or 50 mg/dL. 116. The method of claim 112, wherein the one or more risk factors are selected from age, smoking, high blood pressure, low HDL-cholesterol, and family history of early coronary heart disease. 117. The method of claim 112, wherein the animal fails to achieve LDL-cholesterol target levels following lipid-lowering therapy, fails to comply with recommended therapy, develops treatment side effects, or any combination thereof. 118. The method of claim 117, wherein said lipid-lowering therapy is a statin. 119. The method of claim 117, wherein the lipid-lowering therapy is ezetimibe. 120. The method of claim 96, wherein administering results in ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particles, small VLDL-particles, non-HDL-cholesterol, liver triglyceride levels, serum glycerol A reduction in triglycerides, serum phospholipids, or any combination thereof. 121. The method of claim 120, wherein the reduction in ApoB is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, At least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 122. The method of claim 121, wherein the reduction in ApoB is between 10% and 80%, between 20% and 70%, between 30% and 60%, or between 30% and 70%. 123. The method of claim 120, wherein said LDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 124. The method of claim 120, wherein the reduction in VLDL-cholesterol is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 125. The method of claim 120, wherein said Lp(a) reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 126. The method of claim 120, wherein said small LDL-particle reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 127. The method of claim 120, wherein the small VLDL-particle reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 128. The method of claim 120, wherein said non-HDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 129. The method of claim 120, wherein the reduction in hepatic triglyceride levels is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% , at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 130. The method of claim 120, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum triglycerides. 131. The method of claim 120, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum phospholipids. 132. The method of claim 120 or 131, wherein the serum phospholipid is a serum oxidized phospholipid. 133. The method of claim 96, wherein administering results in a reduction in risk of coronary heart disease, or slowing, halting, or preventing progression of atherosclerosis, or any combination thereof. 134. The method of claim 96, wherein administering results in improved cardiovascular outcome in the human. 135. The method of claim 134, wherein the improved cardiovascular outcome is improved carotid intima-media thickness, improved atheroma thickness, increased HDL-cholesterol, or any combination thereof. 136. The method of claim 96, wherein administering improves hepatic steatosis, resulting in lowered lipids, improved LDL/HDL ratio, or any combination thereof. 137. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having a nucleobase sequence comprising the following parts The long portion is composed of at least 8 consecutive nucleobases complementary to: SEQ ID NO: 3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2 588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 138. The compound of claim 137, wherein the modified oligonucleotide is at least 95% complementary to SEQ ID NO:3. 139. The compound of claim 138, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:3. 140. The compound of claim 137, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2 589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 141. The compound of claim 138, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2 589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, Hybridization occurs within 3727-3751 or 3798-3824, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 142. The compound of claim 139, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2 589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 143. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having a nucleobase sequence comprising the following part, which is the same as At least 8 consecutive nucleobases that are fully complementary to the long portion: the nucleobase of SEQ ID NO: 3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 25 61-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005- 3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 144. The compound of claim 143, wherein the modified oligonucleotide is at least 95% complementary to SEQ ID NO:3. 145. The compound of claim 143, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:3. 146. The compound of claim 143, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275-1302, 1315-1341,1351-1389,1351-1447,1365-1439,1390-1417,1390-1429,1390-1439,1399-1425,1408-1435,1420-1447,1453-1482,1490-1516,1490- 1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533-1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749- 1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911-1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997- 2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170-2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 25612588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-25 9, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 147. The compound of claim 144, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 114-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-25 89, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751 or 3798-3824 Hybridization occurs within, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 148. The compound of claim 145, wherein said modified oligonucleotide is exclusively at the position of SEQ ID NO:3 220-253, 290-321, 377419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275-1302, 1315-1341,1351-1389,1351-1447,1365-1439,1390-1417,1390-1429,1390-1439,1399-1425,1408-1435,1420-1447,1453-1482,1490-1516,1490- 1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533-1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749- 1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911-1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997- 2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170-2177, 2245-2284,2295-2394,2355-2381,2355-2394,2405-2461,2560-2587,2560-2609,2561-2588,2562-2589,2563-2589,2564-2589,2565-2589,2566- 25 89, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, Hybridization occurs within 3727-3751 or 3798-3824, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 149. The compound of claim 137, consisting of a single stranded modified oligonucleotide. 150. The compound of claim 149, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 151. The compound of claim 137, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 152. The compound of claim 151, wherein at least one nucleoside comprises a modified sugar. 153. The compound of claim 152, wherein at least one modified sugar is a bicyclic sugar. 154. The compound of claim 153, wherein at least one modified sugar comprises a 2'-O-methoxyethyl group. 155. The compound of claim 151, wherein at least one nucleoside comprises a modified nucleobase. 156. The compound of claim 155, wherein the modified nucleobase is 5-methylcytosine. 157. The compound of claim 137, wherein said modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a linking 3' wing segment consisting of nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment; and wherein each nucleoside of each wing segment comprises Modified sugars. 158. The compound of claim 157, wherein said modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of 5 linked nucleosides; and a 3' wing segment consisting of 5 linked nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment, wherein each of each wing segment Each nucleoside contains a 2'-O-methoxyethyl sugar; and each internucleoside linkage is a phosphorothioate linkage. 159. The antisense compound of claim 157, wherein the antisense compound is a chimeric oligonucleotide consisting of: a gap segment consisting of 10-18 linked 2'-deoxynucleosides; A 5' wing segment consisting of 1-5 linked nucleosides; and a 3' wing segment consisting of 1-5 linked nucleosides; wherein each nucleoside of the 5' wing segment is is a sugar-modified nucleoside, each nucleoside of the 3' wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 160. The compound of claim 137, wherein said modified oligonucleotide consists of 20 linked nucleosides. 161. A composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and a nucleobase as follows, or a salt thereof and a pharmaceutically acceptable carrier or diluent base sequence, the nucleobase sequence comprising at least 8 consecutive nucleobases selected from the nucleobase sequence of the following group: of SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-25 or 3798-3824 162. The composition of claim 161, wherein said modified oligonucleotide is a single stranded oligonucleotide. 163. The composition of claim 161, wherein said modified oligonucleotide consists of 20 linked nucleosides. 164. A method comprising administering to an animal a modified oligonucleotide consisting of 12-30 linked nucleosides and having a nucleobase sequence comprising the following part, said part Consists of at least 8 contiguous nucleobases complementary to the isometric portion of: SEQ ID NO: 3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-25 or 3798-3824 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 165. The method of claim 164, wherein said animal is a human. 166. The method of claim 165, wherein administering the compound slows progression and/or improves hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, premature coronary heart disease , type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improved cardiovascular outcome, or any combination thereof. 167. The method of claim 164, comprising co-administering said compound and at least one additional therapy. 168. The method of claim 167, wherein said compound and an additional therapy are administered concomitantly. 169. The method of claim 167, wherein the compound and the additional therapy are administered in the same formulation. 170. The method of claim 167, wherein said additional therapy is lipid-lowering therapy. 171. The method of claim 170, wherein the lipid-lowering therapy is a therapeutic lifestyle modification, an HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an MTP inhibitor, an antisense compound targeting ApoB, or any combination thereof . 172. The method of claim 171, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin. 173. The method of claim 171, wherein the cholesterol absorption inhibitor is ezetimibe. 174. The method of claim 171, wherein said additional lipid-lowering therapy comprises an HMG-CoA reductase inhibitor and a cholesterol absorption inhibitor, said HMG-CoA reductase inhibitor is simvastatin, said cholesterol dilution inhibitor It's ezetimibe. 175. The method of claim 171, wherein the antisense compound is ISIS 301012. 176. The method of claim 164, wherein said administering is parenteral. 177. The method of claim 176, wherein said parenteral administration comprises subcutaneous or intravenous administration. 178. The method of claim 164, wherein said administering comprises oral administration. 179. A method comprising administering to patients with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, premature coronary heart disease, acute coronary syndrome, type II diabetes, with blood lipid Disorders of type II diabetes, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, A human with elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol is administered a therapeutically effective amount of a composition comprising a modified oligonucleotide The acid is composed of 12-30 connected nucleosides and has the following nucleobase sequence, which comprises at least 8 consecutive nucleobases complementary to the following equal-length parts: SEQ ID NO:3 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275- 1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533- 1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911- 1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170- 2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-25 or 3798-3824 And wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO:3. 180. The method of claim 164, wherein the animal suffers from hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, acute coronary syndrome, premature coronary heart disease, One or more risk factors for coronary heart disease, type 2 diabetes, type 2 diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, high Fatty acidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated IDL-cholesterol, or elevated non-HDL cholesterol . 181. The method of claim 180, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL. 182. The method of claim 180, wherein administering said compound to said animal reduces LDL-cholesterol levels. 183. The method of claim 182, wherein administering the compound results in LDL-cholesterol levels below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, or 50 mg/dL. 184. The method of claim 180, wherein the one or more risk factors are selected from age, smoking, high blood pressure, low HDL-cholesterol, and family history of early coronary heart disease. 185. The method of claim 180, wherein the animal fails to achieve LDL-cholesterol target levels following lipid-lowering therapy, fails to comply with recommended therapy, develops treatment side effects, or any combination thereof. 186. The method of claim 185, wherein said lipid-lowering therapy is a statin. 187. The method of claim 185, wherein the lipid-lowering therapy is ezetimibe. 188. The method of claim 164, wherein administering results in ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particles, small VLDL-particles, non-HDL-cholesterol, liver triglyceride levels, serum glycerol A reduction in triglycerides, serum phospholipids, or any combination thereof. 189. The method of claim 188, wherein the reduction in ApoB is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, At least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 190. The method of claim 189, wherein the reduction in ApoB is between 10% and 80%, between 20% and 70%, between 30% and 60%, or between 30% and 70%. 191. The method of claim 188, wherein said LDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 192. The method of claim 188, wherein the reduction in VLDL-cholesterol is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 193. The method of claim 188, wherein the reduction in Lp(a) is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 194. The method of claim 188, wherein the small LDL-particle reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 195. The method of claim 188, wherein the reduction in small VLDL-particles is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 196. The method of claim 188, wherein said non-HDL-cholesterol reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 197. The method of claim 188, wherein said reduction in hepatic triglyceride levels is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% , at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 198. The method of claim 188, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum triglycerides. 199. The method of claim 188, wherein administering the pharmaceutical composition results in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% %, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% reduction in serum phospholipids. 200. The method of claim 188 or 199, wherein the serum phospholipid is a serum oxidized phospholipid. 201. The method of claim 164, wherein administering results in a reduction in the risk of coronary heart disease, or slowing, stopping or preventing progression of atherosclerosis, or any combination thereof. 202. The method of claim 164, wherein administering results in improved cardiovascular outcome in the human. 203. The method of claim 202, wherein the improved cardiovascular outcome is improved carotid intima-media thickness, improved atheroma thickness, increased HDL-cholesterol, or any combination thereof. 204. The method of claim 164, wherein administering improves hepatic steatosis, resulting in lowered lipids, improved LDL/HDL ratio, or any combination thereof. 205. A compound comprising a modified oligonucleotide consisting of 12-30 connected nucleosides and having the following nucleobase sequence, said nucleobase sequence comprising a sequence selected from SEQ At least 12 consecutive nucleobases of the nucleobase sequence shown in IDNO: 4-457. 206. The compound of claim 205 consisting of a single stranded modified oligonucleotide. 207. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 80% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 208. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 85% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 209. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 90% complementary to the nucleic acid sequence of encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 210. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 95% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 211. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 99% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 212. The compound of claim 206, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the nucleic acid sequence selected from the nucleic acid sequence shown in SEQ ID NO: 1-3, encoding human PCSK9. 213. The compound of claim 206, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 214. The compound of claim 213, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 215. The compound of claim 206, wherein at least one nucleoside comprises a modified sugar. 216. The compound of claim 215, wherein at least one modified sugar is a bicyclic sugar. 217. The compound of claim 215, wherein at least one modified sugar comprises a 2'-O-methoxyethyl group. 218. The compound of claim 206, wherein at least one nucleoside comprises a modified nucleobase. 219. The compound of claim 218, wherein the modified nucleobase is 5-methylcytosine. 220. The compound of claim 205, wherein said modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a linking 3' wing segment consisting of nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment; and wherein each nucleoside of each wing segment comprises Modified sugars. 221. The compound of claim 220, wherein said modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of 5 linked nucleosides; and a 3' wing segment consisting of 5 linked nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment, wherein each of each wing segment Each nucleoside contains a 2'-O-methoxyethyl sugar; and each internucleoside linkage is a phosphorothioate linkage. 222. The antisense compound of claim 220, wherein the antisense compound is a chimeric oligonucleotide consisting of: a gap segment consisting of 10-18 connected 2'-deoxynucleosides; A 5' wing segment consisting of 1-5 linked nucleosides; and a 3' wing segment consisting of 1-5 linked nucleosides; wherein each nucleoside of the 5' wing segment is is a sugar-modified nucleoside, each nucleoside of the 3' wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 223. The compound of claim 206, wherein said modified oligonucleotide consists of 20 linked nucleosides. 224. A composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides or a salt thereof and a pharmaceutically acceptable carrier or diluent having the following core A base sequence, the nucleobase sequence comprising at least 12 consecutive nucleobases selected from the nucleobase sequences of the nucleobase sequences shown in SEQ ID NO: 4-457. 225. The composition of claim 224, wherein said modified oligonucleotide is a single stranded oligonucleotide. 226. The composition of claim 224, wherein said modified oligonucleotide consists of 20 linked nucleosides. 227. A method comprising administering to an animal a compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and having the following nucleobase sequence, the nucleobase The base sequence comprises at least 12 consecutive nucleobases selected from the nucleobase sequences of the nucleobase sequences shown in SEQ ID NO: 4-457. 228. The method of claim 227, wherein said animal is a human. 229. The method of claim 228, wherein administering the compound slows progression and/or improves hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, premature coronary heart disease , type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improved cardiovascular outcome, or any combination thereof. 230. The method of claim 228, comprising co-administering said compound and at least one additional therapy. 231. The method of claim 230, wherein said compound and an additional therapy are administered concomitantly. 232. The method of claim 230, wherein the compound and the additional therapy are administered in the same formulation. 233. The method of claim 230, wherein said additional therapy is lipid-lowering therapy. 234. The method of claim 233, wherein the lipid-lowering therapy is a therapeutic lifestyle modification, an HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an MTP inhibitor, an antisense compound targeting ApoB, or any combination thereof . 235. The method of claim 234, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin. 236. The method of claim 234, wherein the cholesterol absorption inhibitor is ezetimibe. 237. The method of claim 234, wherein the antisense compound is ISIS 301012. 238. The method of claim 227, wherein said administering is parenteral. 239. The method of claim 228, wherein said parenteral administration comprises subcutaneous or intravenous administration. 240. The method of claim 227, wherein said administering comprises oral administration. 241. The method of claim 227, wherein the animal suffers from hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, acute coronary syndrome, premature coronary heart disease, One or more risk factors for coronary heart disease, type 2 diabetes, type 2 diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, high Fatty acidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated LDL-cholesterol, elevated non-HDL cholesterol, or any combination thereof. 242. The method of claim 241, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL. 243. The method of claim 241, wherein the one or more risk factors are selected from age, smoking, high blood pressure, low HDL-cholesterol, and family history of early coronary heart disease. 244. The method of claim 227, wherein the animal fails to achieve LDL-cholesterol target levels following lipid-lowering therapy, fails to comply with recommended therapy, develops side effects of treatment, or any combination thereof. 245. The method of claim 244, wherein the lipid-lowering therapy is a statin or ezetimibe. 246. The method of claim 227, wherein administering results in ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particles, small VLDL-particles, non-HDL-cholesterol, liver triglyceride levels, serum glycerol A reduction in triglycerides, serum phospholipids, or any combination thereof. 247. The method of claim 246, wherein administering the compound results in an LDL-cholesterol level lower than at least about 190 mg/dL, at least 160 mg/dL, at least 130 mg/dL, at least 100 mg/dL, 70 mg/dL, or 50 mg/dL target level. 248. The method of claim 247, wherein the reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. 249. The method of claim 248, wherein the reduction is between 10% and 80%, between 20% and 70%, between 30% and 60%, or between 30% and 70%. 250. The method of claim 246, wherein said serum phospholipid is serum oxidized phospholipid. 251. The method of claim 229, wherein the improved cardiovascular outcome is improved carotid intima-media thickness, improved atheroma thickness, increased HDL-cholesterol, or any combination thereof. 252. The method of any one of claims 227-251, comprising administering the pharmaceutical composition every day, every two days, every three days, every four days, every five days, every six days, or every seven days. 253. The method of any one of claims 227-251, comprising administering the pharmaceutical composition every week, every two weeks, every three weeks, or every four weeks. 254. The method of any one of claims 227-251, comprising administering the pharmaceutical composition every month, every two months, every three months, every four months, every five months, or every six months. 255. The method of any one of claims 227-251, wherein the dose is 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 270, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, or 800 mg. 256. The method of any one of claims 227-251, wherein the dose is 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 270, 280, 285, 290, 295, or 300 mg. 257. The method of any one of claims 227-251, wherein the dose is 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg. 258. The method of any one of claims 227-251, wherein the pharmaceutical composition comprises a concentration of about 50 mg/ml, about 75 mg/ml, about 100 mg/ml, about 125 mg/ml, about 150 mg/ml, about 175 mg/ml ml, about 200 mg/ml, about 225 mg/ml, or about 250 mg/ml of the antisense oligonucleotide. 259. A method of inhibiting expression of PCSK9 in a human cell or tissue comprising contacting said cell or tissue with a compound comprising a modified oligonucleotide produced by targeting a nucleic acid molecule encoding human PCSK9 , composed of 12-30 linked nucleosides. 260. A treatment for hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, premature coronary heart disease, acute coronary syndrome, one or more risks of coronary heart disease factor, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, The method of metabolic syndrome, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated LDL-cholesterol, atherosclerosis, elevated non-HDL cholesterol, or any combination thereof, by Patients with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, coronary heart disease, premature coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, with Type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, metabolic syndrome, elevated ApoB, A human with elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated ILDL-cholesterol, elevated non-HDL cholesterol, or any combination thereof is administered a compound comprising a modified oligonucleotide that is The nucleotide consists of 12-30 linked nucleosides targeting the nucleic acid molecule encoding human PCSK9. 261. The method of claim 259, wherein treatment results in slowing of progression and/or amelioration of hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, history of coronary heart disease, acute coronary syndrome, coronary heart disease, premature Coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, hypertriglyceridemia Hyperlipidemia, hyperlipidemia, metabolic syndrome, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, elevated IDL-cholesterol, atherosclerosis, non-HDL cholesterol increase, or any combination thereof. 262. The method of claim 259, wherein said compound is 80% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 263. The method of claim 259, wherein said compound is 85% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 264. The method of claim 259, wherein said compound is 90% complementary to the nucleic acid sequence of encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 265. The method of claim 259, wherein said compound is 95% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 266. The method of claim 259, wherein said compound is 99% complementary to the nucleic acid sequence encoding PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 267. The method of claim 259, wherein said compound is 100% complementary to the nucleic acid sequence encoding human PCSK9 selected from the nucleic acid sequences shown in SEQ ID NO: 1-3. 268. The method of claim 259, wherein said compound consists of a single stranded modified oligonucleotide. 269. The method of claim 259, wherein said compound comprises at least one phosphorothioate internucleoside linkage. 270. The method of claim 269, wherein each internucleoside linkage in said compound is a phosphorothioate internucleoside linkage. 271. The method of claim 259, wherein said compound comprises a modified sugar. 272. The method of claim 271, wherein the modified sugar is a bicyclic sugar. 273. The method of claim 272, wherein the modified sugar is 2'-O-methoxyethyl. 274. The method of claim 259, wherein at least one nucleoside of said compound comprises a modified nucleobase. 275. The method of claim 274, wherein the modified nucleobase is 5-methylcytosine. 276. The method of claim 259, wherein said modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; 3' wing segment consisting of nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment; and wherein each nucleoside of each wing segment comprises Modified sugars. 277. The method of claim 259, wherein said modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of 5 linked nucleosides; and a 3' wing segment consisting of 5 linked nucleosides; wherein said gap segment is located between said 5' wing segment and said 3' wing segment, wherein each of each wing segment Each nucleoside contains a 2'-O-methoxyethyl sugar; and each internucleoside linkage is a phosphorothioate linkage. 278. The method of claim 259, wherein said modified oligonucleotide consists of 20 linked nucleosides. 279. The method of claim 259, wherein said administering is parenteral. 280. The method of claim 259, wherein said parenteral administration comprises subcutaneous or intravenous administration. 281. The method of claim 259, wherein said administering comprises oral administration.