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IL302558A - Oligonucleotide compositions and methods thereof - Google Patents

Oligonucleotide compositions and methods thereof

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Publication number
IL302558A
IL302558A IL302558A IL30255823A IL302558A IL 302558 A IL302558 A IL 302558A IL 302558 A IL302558 A IL 302558A IL 30255823 A IL30255823 A IL 30255823A IL 302558 A IL302558 A IL 302558A
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Israel
Prior art keywords
oligonucleotide
nucleic acid
target
composition
oligonucleotides
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IL302558A
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Hebrew (he)
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Wave Life Sciences Ltd
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Publication of IL302558A publication Critical patent/IL302558A/en

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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/11—Antisense
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/335—Modified T or U
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    • C12N2320/00—Applications; Uses
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    • C12N2320/33—Alteration of splicing
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    • C12Y—ENZYMES
    • C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
    • C12Y305/04—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in cyclic amidines (3.5.4)

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  • Medicinal Chemistry (AREA)
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  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Claims (95)

1.WO 2022/099159 PCT/US2021/058495
2.CLAIMS 1. An oligonucleotide comprising: a first domain; and a second domain, wherein:the first domain comprises one or more 2’-F modifications;the second domain comprises one or more sugars that do not have a 2’-F modification;about 30%-70% (e.g., about 30%-60%, 30%-50%, or about 30%, 40%, 50%, 60% or 70%) of sugars in the first domain independently comprise a 2’-F modification; and30%-70% (e.g., about 30%-60%, 30%-50%, or about 30%, 40%, 50%, 60% or 70%) of sugars in the first domain comprises 2’-OR, wherein R is optionally substituted C1-6 aliphatic.2. The oligonucleotide of claim 1, wherein when the oligonucleotide is contacted with a target nucleic acid comprising a target adenosine in a system, a target adenosine in the target nucleic acid is modified, and the modification is or comprises conversion of the target adenosine to an inosine.
3. The oligonucleotide of claim 2, wherein the first domain comprises one or more (e.g., 1-20, 1-15, 1- 14, 1-13, 1-12, 1-11, 1-10, 2-20, 3-15, 4-15, 5-15, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) 2’-F blocks and one or more (e.g., 1-20, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 2-20,3-15,4-15,5- 15, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) separating blocks, wherein each sugar in each 2’-F block is independently a 2’-F modified sugar, and wherein each sugar in each separating block is independently a sugar other than a 2’-F modified sugar.
4. The oligonucleotide of claim 3, wherein there are 3 or more 2’-F blocks in the first domain.
5. The oligonucleotide of claim 4, wherein there are 2 or more separating blocks in the first domain.
6. The oligonucleotide of claim 5, wherein each sugar in a separating block is independently a 2’-ORmodified sugar wherein R is optionally substituted C1-6 aliphatic.
7. The oligonucleotide of claim 5, wherein each block in a first domain that is bonded to a 2’-F block in a first domain is a separating block.
8. An oligonucleotide comprising:a first domain; anda second domain, wherein:the first domain comprises one or more 2’-F modifications;the second domain comprises one or more sugars that do not have a 2’-F modification.
9. An oligonucleotide comprising one or more modified sugars and/or one or more modified internucleotidic linkages, wherein the oligonucleotide comprises a first domain and a second domain each independently comprising one or more nucleobases.
10. The oligonucleotide of claim 8 or 9, wherein when the oligonucleotide is contacted with a target 775 WO 2022/099159 PCT/US2021/058495 nucleic acid comprising a target adenosine in a system, a target adenosine in the target nucleic acid is modified, and the modification is or comprises conversion of the target adenosine to an inosine.
11. The oligonucleotide of claim 7, wherein the oligonucleotide has a length of about 26-35 nucleobases.
12. The oligonucleotide of claim 7, wherein the each of the first and second domain independently has alength of about 10-50 nucleobases.
13. The oligonucleotide of claim 12, wherein about 50%-100% of intemucleotidic linkages in the firstdomain are modified intemucleotidic linkages.
14. The oligonucleotide of claim 13, wherein the second domain comprise a nucleoside opposite to atarget adenosine when the oligonucleotide is aligned with a target nucleic acid for complementarity.
15. The oligonucleotide of claim 14, wherein the opposite nucleobase is optionally substituted orprotected U, or is an optionally substituted or protected tautomer of U, or is optionally substituted or protected C, or is an optionally substituted or protected tautomer of C, or is optionally substituted or protected A, or is an optionally substituted or protected tautomer of A, or is optionally substituted or protected nucleobase of pseudoisocytosine, or is an optionally substituted or protected tautomer of the nucleobase of pseudoisocytosine, or is a nucleobase BA, wherein BA is or comprises Ring BA or a tautomer thereof, wherein Ring BA is an optionally substituted, 5-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 hetereoatoms.
16. The oligonucleotide of claim 15, wherein the nucleobase is BA, wherein BA is or comprises Ring BA or a tautomer thereof, wherein Ring BA is an optionally substituted, 5-20 membered, monocyclic, bicyclic or polycyclic ring having 0-10 hetereoatoms.
17. The oligonucleotide of claim 16, wherein BA has weaker hydrogen bonding with the target adenine of the adenosine compared to U.
18. The oligonucleotide of claim 16, wherein Ring BA comprises =X2=X3 = , =X2=X3=X=, -X׳(=)=X2=X3=. -X1(^^)^^X2^^X3^^X4^^, or has the structure of formula BA-I, BA-I-a, BA-I-b, BA-II, BA-II-a, BA-II-b, BA-III, BA-III-a or BA-III-b.
19. The oligonucleotide of claim 14, wherein the opposite nucleobase is
20. The oligonucleotide of claim 14, wherein the opposite nucleobase
21. The oligonucleotide of claim 14, wherein the opposite nucleobase is 776 WO 2022/099159 PCT/US2021/058495
22. The oligonucleotide of claim 14, wherein about 50%-100% of sugars in the second domain are independently modified sugars with a modification that is not 2’-F.
23. The oligonucleotide of claim 22, wherein about 50%-100% of intemucleotidic linkages in the second domain are modified intemucleotidic linkages.
24. The oligonucleotide of claim 23, wherein each modified intemucleotidic linkages is independently a phosphorothioate intemucleotidic linkage or a non-negatively charged intemucleotidic linkage.
25. The oligonucleotide of claim 24, wherein the second domain comprises one or more phosphorothioate intemucleotidic linkages.
26. The oligonucleotide of claim 25, wherein the second domain comprises 1, 2, 3, 4, or 5 non- negatively charged intemucleotidic linkages.
27. The oligonucleotide of claim 26, wherein the intemucleotidic linkage between the last and the second last nucleosides of the second domain is a non-negatively charged intemucleotidic linkage.
28. The oligonucleotide of claim 25, wherein at least 50%-100% of chiral intemucleotidic linkages in the second domain is chirally controlled.
29. The oligonucleotide of claim 28, wherein the second domain comprises or consists of from the 5’ to 3’ a first subdomain, a second subdomain , and a third subdomain.
30. The oligonucleotide of claim 29, wherein the first subdomain has a length of about 5-50 nucleobases.
31. The oligonucleotide of claim 30, wherein about 5 0%-100% of sugars in the first subdomain areindependently modified sugars with a modification that is not 2’-F.
32. The oligonucleotide of claim 31, wherein the second subdomain has a length of 3 nucleobases.
33. The oligonucleotide of claim 32, wherein the second subdomain comprises a nucleoside opposite to a 777 WO 2022/099159 PCT/US2021/058495 target adenosine.
34. The oligonucleotide of claim 33, wherein the second subdomain comprises one or more natural DNAsugars.
35. The oligonucleotide of claim 34, wherein the second subdomain comprises one or more natural RNAsugars.
36. The oligonucleotide of claim 34, wherein the second subdomain comprises about a 2’-F modifiedsugars.
37. The oligonucleotide of claim 34, wherein the sugar of the opposite nucleoside comprises a 2’-OH.
38. The oligonucleotide of claim 34, wherein the sugar of the opposite nucleoside is a natural DNAsugar.
39. The oligonucleotide of claim 34, wherein the sugar of a nucleoside 5’-next to the opposite nucleoside(sugar of N1 in 5’-...N!N0...3’, wherein when aligned with a target, No is opposite to a target adenosine) is a natural DNA sugar.
40. The oligonucleotide of claim 34, wherein the sugar of a nucleoside 5’-next to the opposite nucleoside(sugar of N1 in 5’-...N!N0...3’, wherein when aligned with a target, No is opposite to a target adenosine) comprises 2’-F.
41. The oligonucleotide of claim 34, wherein the sugar of a nucleoside 3 ’-next to the opposite nucleoside(sugar 0fN-1 in 5’-...N0N-!...3’, wherein when aligned with a target, No is opposite to a target adenosine) is a natural DNA sugar.
42. The oligonucleotide of claim 34, wherein each of the sugar of the opposite nucleoside, the sugar of anucleoside 5’-next to the opposite nucleoside (sugar of N! in 5’-.. .N1N0.. .3’, wherein when aligned with a target, No is opposite to a target adenosine), and the sugar of a nucleoside 3’-next to the opposite nucleoside (sugar 0fN-1 in 5’-...N0N-!...3’, wherein when aligned with a target, No is opposite to a target adenosine) is independently a natural DNA sugar.
43. The oligonucleotide of claim 34, wherein the sugar of the opposite nucleoside is a natural DNAsugar, the sugar of a nucleoside 5’-next to the opposite nucleoside (sugar ofN! in 5’-...N!N0...3’, wherein when aligned with a target, No is opposite to a target adenosine) is a 2’-F modified sugar, and the sugar of a nucleoside 3’-next to the opposite nucleoside (sugar ofN- in 5’-...N0N-!...3’, wherein when aligned with a target, No is opposite to a target adenosine) is a natural DNA sugar.
44. The oligonucleotide of claim 34, wherein the nucleoside opposite to a target nucleoside is connectedto its 3’ immediate nucleoside through a Rp phosphorothioate intemucleotidic linkage.
45. The oligonucleotide of claim 34, wherein the nucleoside (position -1) that is 3’ immediate to annucleoside opposite to a target nucleoside (position 0) is connected to its 3’ immediate nucleoside (position - 2) through a non-negatively charged intemucleotidic linkage.
46. The oligonucleotide of claim 34, wherein the 3’-immediate nucleoside comprises a base that is notG. 778 WO 2022/099159 PCT/US2021/058495
47. The oligonucleotide of claim 34, wherein the 3’-immediate nucleoside comprises hypoxanthine.
48. The oligonucleotide of claim 34, wherein the third subdomain has a length of about 1-10nucleobases.
49. The oligonucleotide of claim 34, wherein the oligonucleotide comprises a moiety that is or comprises GalNAc or a derivative thereof.
50. An oligonucleotide comprising a modified nucleobase or a modified linkage as described herein.
51. An oligonucleotide, wherein the oligonucleotide is otherwise identical to an oligonucleotide of anyone of the preceding claims, except that at a position of a modified internucleotidic linkage is a linkage having the structure of-O 5-PL(RCA)-O3-, wherein:PL is P, or P(=W);Wis O, S, 0rW N;Rca is or comprises an optionally substituted or capped chiral auxiliary moiety, O5 is an oxygen bonded to a 5’-carbon of a sugar, and O3 is an oxygen bonded to a 3’-carbon of a sugar.
52. The oligonucleotide of claim 51, wherein at each position of a modified internucleotidic linkage is independently a linkage having the structure of ־O5-PL(W)(RCA)־O3-.Rc4־/־O -Rc3
53. The oligonucleotide of claim 52, wherein each RCA is independently 'Rc2 orpCK 70־ N—Rc3R^/—Rc2 , wherein RC1 is R, -Si(R)3 or -SO2R, Rc2 and Rc3 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having, in addition to the nitrogen atom, 0-2 heteroatoms, Rc4 is -H or -C(O)R’. □C4 □C4 K t K ؛ ، — 0 N ־ 7 0 N—I ־ 7 CA RC1 / RC1 /
54. The oligonucleotide of claim 52, wherein each R is independently ^'x1' '''/ or .
55. The oligonucleotide of claim 54, wherein RC1 is ־SiPh2Me, or wherein RC1 is -SO2R, wherein R isoptionally substituted phenyl.
56. The oligonucleotide of any one of the preceding claims, wherein the base sequence of the oligonucleotide is or comprises a sequence that differs at no more than 1, 2, 3, 4, or 5 positions from UUCAGUCCCUUUCTCIUCGA, CCCCAGCAGCUUCAGUCCCUUUCTCGUCGA, or CCCAGCAGCUUCAGUCCCUUUCTUIUCGAU, wherein each U can be independently replaced with T and vice versa.
57. An oligonucleotide having the structure ofModOO 1L00 ImCnOO 1 RmC*SmC* SfA*SfG* SmCmA*SfG* SfCmU* SfUnOOIRmC£A* SfGnOO IRfUmC* Sf C* SfC*SfU*SmUmUfC* ST* Sb008U*SIn00 1 SmUfC*SmG* SmAnOOIRmU, wherein: 779 WO 2022/099159 PCT/US2021/058495 LOO 1 is -NH־(CH2)6־, wherein -NH- is connected to ModOO 1;m represents a 2’-OMe modification to a nucleoside; nOOIR represents a Rp nOOl linkage, wherein a nOOl linkage has the structure ofnOOlS represents aSp nOOl linkage;*S represents a Sp phosphorothioate linkage;f represents a 2’-F modification to a nucleoside; b008U represents a nucleoside whose base is । ; andI represents a nucleoside whose base is hypoxanthine.
58. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SmCmA* SfG* SfCmU* SfUnOO IRmCfA* SfGnOO IRfUmC* SfC*SfC*SfUn001RmUmUfC*ST*Sb008U*SIn001SmUfC*SmG*SmAn001RmU, wherein modifications are as described in claim 1496 or the specification.
59. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SmCmAfG* SfCmU* SfUnOO IRmCfA* SfGnOO IRfUmC* SfC* SmCfUn001RmUmUfC*ST*Sb008U*SIn001SmUfC*SmG*SmAn001RmU, wherein modifications are as described in claim 1496 (and/or the specification).
60. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SfCmA* SfG* SmCmU* SfUnOO IRmCfA* SfGnOO IRfUmC* Sf C*SfC* SfUnOO IRfU* SmUfC* ST* Sb008U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
61. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SfCmA* SfG* SfCmU* SfUnOO IRmCfA* SfGnOO IRfUmC* Sm CfC* SfUnOO IRfU* SmUfC* ST* SbOO8U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are 780 WO 2022/099159 PCT/US2021/058495 as described in claim 1496 (and/or the specification).
62. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SmCmAfG* SfC* SfU* SfUnOO IRfC* SfAfGn00 IRfUmCmCfC * SfU* SmUmU* SfC* ST* SbOO8U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
63. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SfCmA* SfG* SfCmU* SfUnOO IRmCfA* SfGnOO IRfUmC* SfC * SfC* SfU* SfU* SmUfC* ST* SbOO8U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
64. An oligonucleotide having the structure ofModOO 1L00 ImCnOO IRmC* SmC* SfA* SfG* SmSCeoAeofG* SfC* STeofUnOO IRmCfA* SfGnOO IRfUmC* S fC* SfC*SfUnOO 1 RTeoTeofC*ST* SbOO8U* SInOO 1 SmUfC*SmG*SmAnOO 1 RmU, wherein modifications are as described in claim 1496 (and/or the specification)
65. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* SmCmAfG* SfC* SmUfUnOO IRmCfA* SmGnOO IRfUmC* SfC *SfC*SfUnOOIRmUmUfC*ST*SbOO8U*SInOO 1 SmUfC*SmG*SmAnOO 1 RmU, wherein modifications are as described in claim 1496 (and/or the specification)
66. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* SfC* STeofUnOO IRmCfA* SmGnOO IRfUmC* SfC* SfC* SfUnOO IRTeoTeofC* ST* SbOO8U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
67. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* SfC* STeofUnOO IRmCfA* SmGnOO 1RfUm5C eo*SfC*SfC*SfUnOOIRTeoTeofC*ST*SbOO8U*SInOO 1 SmUfC*SmG*SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
68. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* SmCTeo* SmUnOO IRmCfA* SfGnOO IRmUm CmC* SfC* SfU* STeoTeofC* ST* SbOO8U* SInOO 1 SmUfC* SmG* SmAnOO IRmU, wherein modifications are as described in claim 1496 (and/or the specification).
69. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* SmCTeo* SmUnOO IRmCfA* SfGnOO IRmUmS CeomC*SfC*SfU*STeoTeofC*ST*SbOO8U*SInOO 1 SmUfC*SmG*SmAnOOIRmU, wherein modifications are as described in claim 1496 (and/or the specification).
70. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* Sm5CcoTco* SmUnOO 1Rm5CcofA* SfGnOO RmUm5Ceom5Ceo*SfC*SfU*STeoTeofC*ST*SbOO8U*SInOO 1 SmUfC*SmG*SmAnOOIRmU, wherein 781 WO 2022/099159 PCT/US2021/058495 modifications are as described in claim 1496 (and/or the specification).
71. An oligonucleotide having the structure ofModOOlLOO ImCnOO IRmC* SmC* SfA* SfG* Sm5CcoAcofG* SfC* SmUmUnO01RmCfA* SfGn00 lRfUm5C eo* SfC* SmCmUnOO IRmUTeofC* ST* Sb008U* SInOO 1 SmUfC* SmG* SmAnOO 1RmU, wherein modifications are as described in claim 1496 (and/or the specification).
72. An oligonucleotide having the structure ofModOOlLOO ImCnOO 1RmC* SmC* SfA* SfG* Sm5CeoAeofG* SfC* STeofUnOO IRmCfA* SfGn00 1RfUm5Ce o* SfC* SfC* SfUn00 IRTeoTeofC* ST* Sb008U* SInOO 1 SmUfC* SmG* SmAnOO 1RmU, wherein modifications are as described in claim 1496 (and/or the specification).
73. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide is in a salt form.
74. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide is in apharmaceutically acceptable salt form.
75. The oligonucleotide of any one of the preceding claims, wherein diastereomeric excess of each chirallinkage phosphorus is independently about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.
76. The oligonucleotide of any one of claims 1-75, wherein the oligonucleotide has a purity of about 10%-100%.
77. A pharmaceutical composition which comprises or delivers an effective amount of an oligonucleotide of any one of claims 1-76 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
78. An oligonucleotide composition comprising a plurality of oligonucleotides, wherein oligonucleotides of the plurality share:1) a common base sequence, and2) the same linkage phosphorus stereochemistry independently at one or more chiral internucleotidic linkages (“chirally controlled internucleotidic linkages ”);wherein each oligonucleotide of the plurality is independently an oligonucleotide of any one of claims 1-76 or an acid, base, or salt form thereof; oran oligonucleotide composition comprising one or more pluralities of oligonucleotides, wherein oligonucleotides of each plurality independently share:1) a common base sequence, and2) the same linkage phosphorus stereochemistry independently at one or more chiral internucleotidic linkages (“chirally controlled internucleotidic linkages ”);wherein each oligonucleotide of the plurality is independently an oligonucleotide of any one of claims 1-76 or an acid, base, or salt form thereof; ora composition comprising a plurality of oligonucleotides which are of a particular oligonucleotide type characterized by: 782 WO 2022/099159 PCT/US2021/058495 a) a common base sequence;b) a common pattern of backbone linkages;c) a common pattern of backbone chiral centers;d) a common pattern of backbone phosphorus modifications;which composition is chirally controlled in that it is enriched, relative to a substantially racemic preparation of oligonucleotides having the same common base sequence, pattern of backbone linkages and pattern of backbone phosphorus modifications, for oligonucleotides of the particular oligonucleotide type, or a non-random level of all oligonucleotides in the composition that share the common base sequence are oligonucleotides of the plurality; andwherein each oligonucleotide of the plurality is independently an oligonucleotide of any one of claims 1-76 or an acid, base, or salt form thereof; oran oligonucleotide composition comprising a plurality of oligonucleotides, wherein oligonucleotides of the plurality share:1) a common base sequence, and2) the same linkage phosphorus stereochemistry independently at one or more chiral internucleotidic linkages (“chirally controlled internucleotidic linkages ”);wherein the common base sequence is complementary to a base sequence of a portion of a nucleic acid which portion comprises a target adenosine; oran oligonucleotide composition comprising one or more pluralities of oligonucleotides, wherein oligonucleotides of each plurality independently share:1) a common base sequence, and2) the same linkage phosphorus stereochemistry independently at one or more chiral internucleotidic linkages (“chirally controlled internucleotidic linkages ”);wherein the common base sequence of each plurality is independently complementary to a base sequence of a portion of a nucleic acid which portion comprises a target adenosine; ora composition comprising a plurality of oligonucleotides which are of a particular oligonucleotide type characterized by:a) a common base sequence;b) a common pattern of backbone linkages;c) a common pattern of backbone chiral centers;d) a common pattern of backbone phosphorus modifications;which composition is chirally controlled in that it is enriched, relative to a substantially racemic preparation of oligonucleotides having the same common base sequence, pattern of backbone linkages and pattern of backbone phosphorus modifications, for oligonucleotides of the particular oligonucleotide type, or a non-random level of all oligonucleotides in the composition that share the common base sequence are oligonucleotides of the plurality; and 783 WO 2022/099159 PCT/US2021/058495 wherein the common base sequence is complementary to a base sequence of a portion of a nucleic acid which portion comprises a target adenosine.
79. The composition of claim 78, wherein each oligonucleotide of the plurality is independently an oligonucleotide of any one of claims 57-72 or a pharmaceutically acceptable salt thereof.
80. The composition of any one of claims 78-79, wherein the level of oligonucleotides of a plurality in oligonucleotides in the composition that share the common base sequence of the plurality is about or at least about (DS)nc , wherein DS is about 85%-100% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% or more) and nc is the number of chirally controlled internucleotidic linkages, or wherein the level of oligonucleotides of a plurality in oligonucleotides in the composition that share the same constitution as an oligonucleotide of the plurality or a salt thereof is about or at least about (DS)nc , wherein DS is about 85%-100% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% or more) and nc is the number of chirally controlled internucleotidic linkages
81. A phosphoramidite, wherein the nucleobase of the phosphoramidite is a nucleobase as described herein or a tautomer thereof, wherein the nucleobase or tautomer thereof is optionally substituted or protected, ora phosphoramidite, wherein the nucleobase is or comprises Ring BA, wherein Ring BA has the structure of BA-I, BA-I-a, BA-I-b, BA-II, BA-II-a, BA-II-b, BA-III, BA-III-a, BA-III-b, BA-IV, BA-IV-a, BA-IV-b, BA-V, BA-V-a, BA-V-b, or BA-VI, or a tautomer of Ring BA, wherein the nucleobase is optionally substituted or protected.
82. The phosphoramidite of claim 81, wherein the phosphoramidite has the structure of Rns-P(OR)N(R)2, wherein RNS is a optionally protected nucleoside moiety, and each R is as described herein, preferably wherein phosphoramidite has the structure of RNS־P(OCH2CH2CN)N(i-Pr)2.
83. The phosphoramidite of claim 81, wherein the phosphoramidite comprises a chiral auxiliary moiety, wherein the phosphorus is bonded to an oxygen and a nitrogen atom of the chiral auxiliary moiety, preferably rns rns I I R ZP O N—1 o N—،RC1 ל V Rc1^ Zwherein the phosphoramidite has the structure of or .
84. The phosphoramidite of claim 83, wherein RC1 is -SiPh2Me.
85. The phosphoramidite of claim 83, wherein RC1 is -SO2R, wherein R is optionally substituted Choaliphatic or wherein R is optionally substituted phenyl.
86. A method for preparing an oligonucleotide or composition, comprising coupling a 5’-OH of an oligonucleotide or a nucleoside with a phosphoramidite of any one of claims 81-85.
87. A method for characterizing an oligonucleotide or a composition, comprising: administering the oligonucleotide or composition to a cell or a population thereof comprising or 784 WO 2022/099159 PCT/US2021/058495 expressing an AD ARI polypeptide or a characteristic portion thereof, or a polynucleotide encoding anAD ARI polypeptide or a characteristic portion thereof; oradministering the oligonucleotide or composition to a non-human animal or a population thereof comprising or expressing an ADAR1 polypeptide or a characteristic portion thereof, or a polynucleotide encoding an AD ARI polypeptide or a characteristic portion thereof.
88. A method for modifying a target adenosine in a target nucleic acid, comprising contacting the target nucleic acid with an oligonucleotide or composition of any one of the preceding claims; ora method for deaminating a target adenosine in a target nucleic acid, comprising contacting the target nucleic acid with an oligonucleotide or composition of any one of the preceding claims; ora method for producing, or restoring or increasing level of a product of a particular nucleic acid, comprising contacting a target nucleic acid with an oligonucleotide or composition of any one of the preceding claims, wherein the target nucleic acid comprises a target adenosine, and the particular nucleic acid differs from the target nucleic acid in that the particular nucleic acid has an I or G instead of the target adenosine; ora method for reducing level of a product of a target nucleic acid, comprising contacting a target nucleic acid with an oligonucleotide or composition of any one of the preceding claims, wherein the target nucleic acid comprises a target adenosine; ora method, comprising:contacting an oligonucleotide or composition of any one of the preceding claims with a sample comprising a target nucleic acid and an adenosine deaminase, wherein:the base sequence of the oligonucleotide or oligonucleotides in the oligonucleotide composition is substantially complementary to that of the target nucleic acid; andthe target nucleic acid comprises a target adenosine;wherein the target adenosine is modified; ora method, comprising1) obtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; and2) obtaining a reference level of modification of a target adenosine in a target nucleic acid, which level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein: 785 WO 2022/099159 PCT/US2021/058495 oligonucleotides of the first plurality comprise more sugars with 2’-F modification, more sugars with 2’-OR modification wherein R is not -H, and/or more chiral intemucleotidic linkages than oligonucleotides of the reference plurality; andthe first oligonucleotide composition provides a higher level of modification compared to oligonucleotides of the reference oligonucleotide composition; ora method, comprisingobtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; andwherein the first level of modification of a target adenosine is higher than a reference level of modification of the target adenosine, wherein the reference level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein:oligonucleotides of the first plurality comprise more sugars with 2’-F modification, more sugars with 2’-OR modification wherein R is not -H, and/or more chiral intemucleotidic linkages than oligonucleotides of the reference plurality; ora method, comprising1) obtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; and2) obtaining a reference level of modification of a target adenosine in a target nucleic acid, which level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein:oligonucleotides of the first plurality comprise more sugars with 2’-F modification, more sugars with 2-OR modification wherein R is not -H, and/or more chirally controlled chiral intemucleotidic linkages than oligonucleotides of the reference plurality; and 786 WO 2022/099159 PCT/US2021/058495 the first oligonucleotide composition provides a higher level of modification compared to oligonucleotides of the reference oligonucleotide composition; ora method, comprisingobtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; andwherein the first level of modification of a target adenosine is higher than a reference level of modification of the target adenosine, wherein the reference level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein:oligonucleotides of the first plurality comprise more sugars with 2’-F modification, more sugars with 2-OR modification wherein R is not -H, and/or more chirally controlled chiral intemucleotidic linkages than oligonucleotides of the reference plurality; ora method, comprising1) obtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; and2) obtaining a reference level of modification of a target adenosine in a target nucleic acid, which level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein:oligonucleotides of the first plurality comprise one or more chirally controlled chiral intemucleotidic linkages; andoligonucleotides of the reference plurality comprise no chirally controlled chiral intemucleotidic linkages (a reference oligonucleotide composition is a “stereorandom composition); andthe first oligonucleotide composition provides a higher level of modification compared to oligonucleotides of the reference oligonucleotide composition; or 787 WO 2022/099159 PCT/US2021/058495 a method, comprisingobtaining a first level of modification of a target adenosine in a target nucleic acid, which level is observed when a first oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the first oligonucleotide composition comprises a first plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid; andwherein the first level of modification of a target adenosine is higher than a reference level of modification of the target adenosine, wherein the reference level is observed when a reference oligonucleotide composition is contacted with a sample comprising the target nucleic acid and an adenosine deaminase, wherein the reference oligonucleotide composition comprises a reference plurality of oligonucleotides sharing the same base sequence which is substantially complementary to that of the target nucleic acid;wherein:oligonucleotides of the first plurality comprise one or more chirally controlled chiral intemucleotidic linkages; andoligonucleotides of the reference plurality comprise no chirally controlled chiral intemucleotidic linkages (a reference oligonucleotide composition is a “stereorandom composition).
89. The method of claim 88, wherein a first oligonucleotide composition is an oligonucleotide composition of any one of the preceding claims.
90. The method of any one of claims 86-88, wherein the deaminase is an ADAR enzyme.
91. The method of any one of claims 87-90, wherein the target nucleic acid is more associated with acondition, disorder or disease, or decrease of a desired property or function, or increase of an undesired property or function, compared to a nucleic acid which differs from the target nucleic acid in that it has an I or G at the position of the target adenosine instead of the target adenosine.
92. The method of claim 91, wherein the target adenosine is a G to A mutation.
93. A method for preventing or treating a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto or suffering therefrom an effective amount of an oligonucleotide or composition of any one of the preceding claims; ora method for preventing or treating a condition, disorder or disease associated with a G to A mutation, comprising administering or delivering to a subject susceptible thereto or suffering therefrom an effective amount of an oligonucleotide or composition of any one of the preceding claims.
94. The method of claim 93, wherein the condition, disorder or disease is amenable to an A to G or A to I modification.
95. A compound, oligonucleotide, composition or method of the specification or any one of Example Embodiments 1-1905. 788
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