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WO2024254319A1 - Thérapie génique pour le déficit en lipase acide lysosomale (lal-d) - Google Patents

Thérapie génique pour le déficit en lipase acide lysosomale (lal-d) Download PDF

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Publication number
WO2024254319A1
WO2024254319A1 PCT/US2024/032823 US2024032823W WO2024254319A1 WO 2024254319 A1 WO2024254319 A1 WO 2024254319A1 US 2024032823 W US2024032823 W US 2024032823W WO 2024254319 A1 WO2024254319 A1 WO 2024254319A1
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raav
lipa
composition
polynucleotide
liver
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PCT/US2024/032823
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Paul Taylor Martin
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Research Institute At Nationwide Children's Hospital
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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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/18—Carboxylic ester hydrolases (3.1.1)
    • C12N9/20—Triglyceride splitting, e.g. by means of lipase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01013—Sterol esterase (3.1.1.13)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0362—Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
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    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination

Definitions

  • the disclosure provides gene therapy vectors, such as adeno-associated virus (AAV), designed for treatment of Lysosomal Acid Lipase Deficiency (LAL-D) disorders, such as Wolman disease and cholesteryl ester storage disease (CESD), and disorder related to lipid storage or accumulation, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
  • AAV adeno-associated virus
  • LAL-D Lysosomal Acid Lipase Deficiency
  • CECD cholesteryl ester storage disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the disclosed rAAV provide a wild type human lipase A (LIPA) cDNA under the control of a liver-specific promoter, such as LP1, to a subject in need which results in expression of the wild type human LAL protein.
  • LIPA human lipase A
  • Lysosomal Acid Lipase Deficiency is a lysosomal storage disorder caused by recessive mutations in the Lipase A (LIPA) gene that result in a failure of the lysosomal acid lipase (LAL) protein to sufficiently hydrolyze cholesterol esters into free cholesterol and triglycerides into free fatty acids in the lysosome.
  • LIPA Lipase A
  • LAL occupies a critical and essential position in the control of plasma lipoprotein levels and in the prevention of cellular lipid overload, especially in the liver and spleen (Li et al., Arterioscler Thromb Vasc Biol 39: 850- 856, 2019; Aguisanda et al. Curr Chem Genom Transl Med 11: 1-18, 2017).
  • the LIPA gene is the only gene with this lysosomal function in the human genome.
  • LAL-D is a rare genetic disease, with prevalence ranging from 1 in 40,000 to 1 in 300,000, though disease incidence may be underestimated through failed diagnosis in some instances (Pastores et al., Lysosomal Acid Lipase Deficiency: Therapeutic Options.
  • CESD cholesteryl ester storage disease
  • a polynucleotide comprising (a) one or more liver-specific regulatory control elements and (b) LIPA cDNA sequence.
  • the regulatory control element is a liver specific LP1 promoter comprising a nucleotide sequence set forth in SEQ ID NO: 3, or fragments thereof which retain regulatory control or promoter activity.
  • the vector comprises a late SV40 poly adenylation sequence.
  • the LIPA cDNA is the LIPA variant 1 cDNA, and the LIPA cDNA comprises the polynucleotide sequence set forth in SEQ ID NO: 1.
  • the vector comprises a nucleotide sequence that has about at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotides of 1853-4094 of SEQ ID NO: 4.
  • the plasmid set forth in SEQ ID NO 4 further comprises kanamycin resistance and an origin of replication.
  • described herein is a recombinant adeno-associated virus (rAAV) having a genome comprising a polynucleotide sequence described herein.
  • the rAAV is of the serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVRH10, AAVrh74, AAVrh, AAV11, AAV12, AAV13, Anc80, AAV7m8, or their derivatives.
  • the genome of the rAAV comprises an LP1 promoter and LIPA cDNA.
  • An exemplary genome comprises the LP1 promoter, and the LIPA cDNA such as the rscAAVrh74.LP1.LIPA, the rAAV set out as nucleotides 1853-4094 of SEQ ID NO: 4.
  • the disclosed composition may be formulated for any means of delivery, such as direct injection into the cerebrospinal fluid, intracerebroventricular delivery, intrathecal delivery, intraperitoneal delivery, intraarterial delivery, or intravenous delivery.
  • the disclosed composition is formulated for intravenous delivery or intraperitoneal delivery and comprises a dose of rAAV or rAAV particles of about 1e12 vg/kg to about 8x10 13 vg/kg.
  • Methods of treating LAL-D or a disorder related to lipid storage or accumulation in a subject in need thereof comprising administering a polynucleotide, an rAAV, or an rAAV particle described herein are specifically contemplated.
  • the methods further comprise administering an immunosuppressing agent prior to, after, or simultaneously with the polynucleotide, rAAV, or rAAV particle.
  • the LAL-D includes a disorder or disease caused by a mutation in the LIPA gene, such as Wolman disease or cholesteryl ester storage disease (CESD).
  • the disorder related to lipid storage or accumulation include coronary artery disease, atherosclerosis, type II diabetes, obesity, or nonalcoholic fatty liver disease (NAFLD).
  • Treatment of LAL-D or a disorder related to lipid storage of accumulation in a subject may include reduction of lipid or triglyceride content in the liver of the subject and/or increasing or extending survival of the subject.
  • the disclosure also provides for methods of treating dyslipidemia or hypercholesterolemia in a subject in need thereof comprising administering a polynucleotide, an rAAV or an rAAV particle described herein are specifically contemplated. In some embodiments, the methods further comprise administering an immunosuppressing agent prior to, after, or simultaneously with the polynucleotide, rAAV, or rAAV particle. [0020] The disclosure also provides for method of decreasing triglycerides, cholesterol, and/or fatty acids in a subject in need thereof comprising administering a polynucleotide, an rAAV, or an rAAV particle described herein are specifically contemplated.
  • the methods further comprise administering an immunosuppressing agent prior to, after, or simultaneously with the polynucleotide, rAAV, or rAAV particle.
  • the polynucleotide, rAAV, rAAV particle, or composition are intravenously delivered to the subject.
  • the method further comprises a step of administering an immunosuppressing agent.
  • the polynucleotide, rAAV, rAAV particle, or composition is administered simultaneously, prior to, or after administration of an immunosuppressing agent, such as prednisone, prednisolone, rapamycin, methotrexate, myophenolate mofetil, tacrolimus, mycophenolate, or rituximab.
  • an immunosuppressing agent such as prednisone, prednisolone, rapamycin, methotrexate, myophenolate mofetil, tacrolimus, mycophenolate, or rituximab.
  • the subject has a mutation in the LIPA gene. These mutations include those currently known, such as those set out in Table 1 herein, or a mutation(s) in the LIPA gene identified in the future that is associated with LAL-D.
  • a "subject," as used herein, can be any animal, and may also be referred to as the patient.
  • the subject is a vertebrate animal, and more preferably the subject is a mammal, such as a domesticated farm animal (e.g., cow, horse, goat, pig) or pet (e.g., dog, cat, hamster, chinchilla).
  • the subject is a human.
  • the subject is a pediatric subject.
  • the subject is a pediatric subject, such as a subject ranging in age from 1 to 10 years or the subject is an infant ranging in age for one month to 12 months.
  • the subject is 4 to 15 years of age.
  • the subject in one embodiment, is an adolescent subject, such as a subject ranging in age from 10 to 19 years.
  • LP1 may be a safer gene therapy in LALD patients, particularly in patients where all enzyme expression has been lost (e.g., infants with Wolman disease).
  • rscAAV.LP1.LIPA not only allows for liver-specific gene expression, but it increases gene expression of LIPA in the liver 36-fold compared to the previous miniCMV technology. Because of this, much more LIPA protein is secreted from the liver, providing enzyme replacement therapy (ERT) for organs throughout the body. Because LIPA is a lysosomal enzyme, it can be secreted into the serum and then reinternalized in other organs and correctly targeted back to the lysosome in those organs. This is the concept of ERT protein therapy for lysosomal storage disorders.
  • the present disclosure seeks to utilize this concept with gene therapy, where a single intravenous (IV) treatment will lead to permanent elevations in the lysosomal enzyme.
  • IV intravenous
  • LALD patients complain that the frequency required for ERT therapy, with perfusion every 1- 2 weeks for their entire lifetime, is a major impediment to their quality of life.
  • This disclosure shows that the use of LP1 leads to 5-10 times the normal wild type amount of LIPA enzyme activity in non-liver organs, including spleen, lung, kidney, with even some enzyme elevation in the brain.
  • This increased enzyme activity in non-liver tissues allows for superior long-term treatment in LALD patients.
  • the present disclosure also show that the same biological effects can be achieved at a lower dose (2x10 13 vg/kg), a dose where miniCMV begins to lose some potency.
  • the improved technology of the present disclosure should allow for a dramatic clinical improvement over miniCMV in LALD patients, as miniCMV cannot elevate enzyme activity in non-liver tissues to nearly the same extent. It also may dramatically improve treatment of infants with Wolman disease, as secreted protein in the liver may provide ERT even as hepatocytes divide and AAV genomes are lost during liver growth. Lam et al. showed that miniCMV promoter, while therapeutic when dosed at postnatal day 2, lost potency over time.
  • LIPA Mutations [0052] The LIPA gene is located on human chromosome 10q23.2–23.3 and consists of 10 exons spread over approximately 38 kb. LIPA has 3 transcript variants: Variant 2 (NM_000235) lacks an internal segment in the 5’ UTR compared with variant 1 (NM_001127605). The two variants encode the same protein isoform in size of 399 amino acids (AAs), which has been experimentally validated by cDNA cloning (Baratta et al., World J Gastroenterol 25: 4172-4180).
  • the annotated variant 3 (NM_001288979) lacks two consecutive exons in the 5’ region, which results in translation initiation at a downstream AUG and presumably a shorter protein isoform consists of 283 AAs. (Li and Zhang, Arterioscler Thromb Vasc Biol.39(5): 850–856, 2019). [0053] There are at least 59 known mutations in the LIPA gene. Examples of these mutations are provided in Table 1 below.
  • AAV is a standard abbreviation for adeno-associated virus.
  • Adeno-associated virus is a single-stranded DNA parvovirus that grows only in cells in which certain functions are provided by a co-infecting helper virus.
  • General information and reviews of AAV can be found in, for example, Carter, 1989, Handbook of Parvoviruses, Vol. 1, pp.169-228, and Berns, 1990, Virology, pp.1743-1764, Raven Press, (New York).
  • An "AAV vector” as used herein refers to a vector comprising one or more polynucleotides of interest (or transgenes) that are flanked by AAV terminal repeat sequences (ITRs).
  • AAV virion or "AAV viral particle” or “AAV vector particle” refers to a viral particle composed of at least one AAV capsid protein and an encapsidated polynucleotide AAV vector. If the particle comprises a heterologous polynucleotide (i.e., a polynucleotide other than a wild-type AAV genome such as a transgene to be delivered to a mammalian cell), it is typically referred to as an "AAV vector particle” or simply an "AAV vector”.
  • a heterologous polynucleotide i.e., a polynucleotide other than a wild-type AAV genome such as a transgene to be delivered to a mammalian cell
  • the rAAV genomes provided herein comprises a polynucleotide that at least: 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the nucleotide sequences of nucleotides 1853-4094 of SEQ ID NO: 4.
  • rAAV genomes provided herein in some embodiments, a polynucleotide sequence that encodes an LAL protein and that hybridizes under stringent conditions to the polynucleotide sequence set forth in SEQ ID NO: 1 or the complement thereof.
  • DNA plasmids of the disclosure comprise rAAV genomes of the disclosure.
  • the DNA plasmids are transferred to cells permissible for infection with a helper virus of AAV (e.g., adenovirus, E1-deleted adenovirus, or herpesvirus) for assembly of the rAAV genome into infectious viral particles.
  • AAV e.g., adenovirus, E1-deleted adenovirus, or herpesvirus
  • a helper virus of AAV e.g., adenovirus, E1-deleted adenovirus, or herpesvirus
  • the AAV rep and cap genes may be from any AAV serotype for which recombinant virus can be derived and may be from a different AAV serotype than the rAAV genome ITRs, including, but not limited to, AAV serotypes AAV-9, AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAVrh.74, AAV-8, AAV-10, AAV-11, AAV-12, and AAV-13.
  • Production of pseudotyped rAAV is disclosed in, for example, WO 01/83692 which is incorporated by reference herein in its entirety.
  • a method of generating a packaging cell is to create a cell line that stably expresses all the necessary components for AAV particle production.
  • a plasmid (or multiple plasmids) comprising a rAAV genome lacking AAV rep and cap genes, AAV rep and cap genes separate from the rAAV genome, and a selectable marker, such as a neomycin resistance gene, are integrated into the genome of a cell.
  • AAV genomes have been introduced into bacterial plasmids by procedures such as GC tailing (Samulski et al., 1982, Proc. Natl. Acad. S6.
  • the packaging cell line is then infected with a helper virus such as adenovirus.
  • a helper virus such as adenovirus.
  • packaging cells are cells that are not transformed cancer cells, such as low passage 293 cells (human fetal kidney cells transformed with E1 of adenovirus), MRC-5 cells (human fetal fibroblasts), WI- 38 cells (human fetal fibroblasts), Vero cells (monkey kidney cells), and FRhL-2 cells (rhesus fetal lung cells).
  • the rAAV may be purified by methods standard in the art such as by column chromatography or cesium chloride gradients. Methods for purifying rAAV vectors from helper virus are known in the art and include methods disclosed in, for example, Clark et al., Hum. Gene Ther., 10(6): 1031-1039 (1999); Schenpp and Clark, Methods Mol.
  • compositions provided herein comprise rAAV and a pharmaceutically acceptable excipient or excipients.
  • Acceptable excipients are nontoxic to recipients and are preferably inert at the dosages and concentrations employed, and include, but are not limited to, buffers such as phosphate (e.g., phosphate-buffered saline (PBS)), citrate, or other organic acids; antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt- forming counterions such as sodium; and/or nonionic surfactants such as Tween, copolymers such as poloxamer 188, pluronics (e.g
  • Dosages are expressed in units of vg/kg. Dosages contemplated herein include about 1x10 11 vg/kg, about 1x10 12 vg/kg, about 5x10 12 vg/kg, about 1x10 13 vg/kg, about 1.1x10 13 vg/kg, about 1.2x10 13 vg/kg, about 1.3x10 13 vg/kg, about 1.5x10 13 vg/kg, about 2 x10 13 vg/kg, about 2.5 x10 13 vg/kg, about 3 x 10 13 vg/kg, about 3.5 x 10 13 vg/kg, about 4x 10 13 vg/kg, about 4.5x 10 13 vg/kg, about 5 x 10 13 vg/kg, about 6x10 13 vg/kg, about 7 x10 13 vg/kg, to about 8x10 13 vg/kg.
  • an effective dose is a dose that alleviates (eliminates or reduces) at least one symptom associated with the disorder/disease state being treated, that slows or prevents progression to a disorder/disease state, that slows or prevents progression of a disorder/disease state, that diminishes the extent of disease, that results in remission (partial or total) of disease, and/or that prolongs survival.
  • Example of a LAL-D contemplated for prevention or treatment with methods of the disclosure is Wolman disease and cholesteryl ester storage disease (CESD) or a disorder related to lipid storage or accumulation such as coronary artery disease, atherosclerosis, type II diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), dyslipidemia, or hypercholesterolemia.
  • Combination therapies are also contemplated by the disclosure. Combination as used herein includes both simultaneous treatment and sequential treatments. Combinations of methods of the disclosure with standard medical treatments are specifically contemplated, as are combinations with novel therapies.
  • the combination therapy comprises administering an immunosuppressing agent in combination with the gene therapy disclosed herein.
  • Administration of an effective dose of the compositions may be by routes standard in the art including, but not limited to, intramuscular, parenteral, intravenous, intraarterial, intraperitoneal, oral, buccal, nasal, pulmonary, intracranial, intraosseous, intraocular, rectal, or vaginal.
  • Route(s) of administration and serotype(s) of AAV components of the rAAV (in particular, the AAV ITRs and capsid protein) of the disclosure may be chosen and/or matched by those skilled in the art taking into account the infection and/or disease state being treated and the target cells/tissue(s) that are to express the wild type LAL protein.
  • the disclosure provides for local administration and systemic administration of an effective dose of rAAV and compositions of the disclosure.
  • systemic administration is administration into the circulatory system so that the entire body is affected.
  • Systemic administration includes enteral administration such as absorption through the gastrointestinal tract and parenteral administration through injection, infusion, or implantation.
  • Transduction of cells with rAAV of the disclosure results in sustained expression of the LAL protein.
  • the present disclosure thus provides methods of administering/delivering rAAV which express LAL protein to an animal, preferably a human being. These methods include transducing cells with one or more rAAV of the present disclosure.
  • Exemplary janus kinase inhibitors include tofacitinib, baricitinib, upadacitinib, peficitinib, and oclacitinib.
  • Calcineurin inhibitors bind to cyclophilin and inhibits the activity of calcineurin.
  • Exemplary calcineurine inhibitors includes cyclosporine, tacrolimus and picecrolimus.
  • mTOR inhibitors reduce or inhibit the serine/threonine-specific protein kinase mTOR.
  • Exemplary mTOR inhibitors include rapamycin (also known as sirolimus), everolimus, and temsirolimus.
  • immunosuppressing biologics include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinenumab, vedolizumab, basiliximab, belatacep, and daclizumab.
  • the immunosuppressing agent is an anti-CD20 antibody.
  • anti-CD20 specific antibody refers to an antibody that specifically binds to or inhibits or reduces the expression or activity of CD20.
  • anti-CD20 antibodies include rituximab, ocrelizumab, or ofatumumab.
  • immuosuppressing antibodies include anti-CD25 antibodies (or anti-IL2 antibodies or anti-TAC antibodies) such as basiliximab and daclizumab, and anti- CD3 antibodies such as muromonab-CD3, otelixizumab, teplizumab, and visilizumab, anti- CD52 antibodies such as alemtuzumab.
  • anti-CD25 antibodies or anti-IL2 antibodies or anti-TAC antibodies
  • anti- CD3 antibodies such as muromonab-CD3, otelixizumab, teplizumab, and visilizumab
  • anti- CD52 antibodies such as alemtuzumab.
  • mice develop hepatosplenomegaly, elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and elevated liver and spleen cholesterol and triglycerides.
  • AST serum aspartate aminotransferase
  • ALT alanine aminotransferase
  • liver and spleen cholesterol and triglycerides are elevated.
  • Lipa -/- mice have profound disease by 4 months, showing a 3- to 6-fold increase in the size of the liver and the spleen.
  • Mice succumb to disease several months thereafter, beginning at 6 months of age.
  • Mice The lal ⁇ / ⁇ mice were first generated by Du et al in 1998. The mouse model has been widely used to study the role of Lal in multiple organ systems.
  • mice were dosed at 2 months of age, a time when disease is already present and clearly significant, and assayed for at 6 months of age, 4 months after treatment, a point by which LALD disease is quite severe (most mice begin to perish from the disease between 6 and 7 months of age).
  • the first phenotype investigated was hepatosplenomegaly (Figure 3). Liver and spleen size increased dramatically in untreated Lipa -/- mice relative to wild type, such that the liver is about 4.8 times normal size by 6 months of age.
  • Example 7 LP1 Shows Improved Ability to Induce and Sustain LIPA Gene Expression in Liver [00114] LIPA transgene expression, relative to endogenous mouse wild type Lipa gene expression, in various tissues of Lipa -/- mice was analyzed. Mice were treated intravenously (IV) at 2 months, with analysis at 6 months of age.
  • scAAV.LP1.LIPA induced gene expression in the liver is 216 times normal wild type mouse liver Lipa gene expression, while scAAV.miniCMV.LIPA induced gene expression is only 6 times normal. So scAAV.LP1.LIPA yields 36 times more gene expression in the liver, despite showing lower AAV transduction (see Figure 6). scAAV.LP1.LIPA expression in other organs (e.g., muscle, lung, kidney, and heart) is quite low, consistent with the liver-specific nature of the LP1 promoter. [00115] Thus, scAAV.LP1.LIPA showed a profoundly improved ability to induce and sustain LIPA gene expression in the liver.
  • scAAV.LP1.LIPA also showed much lower LIPA gene expression in all non-liver tissues, perhaps except the lymph node. This data was consistent with the fact that LP1 is a “liver-specific” promoter. As known from previous studies of Factor VIII and Factor IX expression for Hemophilia gene therapy, confinement of gene expression to the liver can greatly suppress both B and T cell responses to the transgenic protein in animals where the endogenous gene has been completely knocked out (as is the present case). [00116] Because LP1 drove such high gene expression in the liver, it is suspected that this would induce increased LIPA enzyme secretion from the liver, which would be manifested as increased enzyme replacement (protein) therapy in non-liver organs.
  • protein enzyme replacement
  • FIG. 8 shows LIPA enzyme activity in tissues after intravenous (IV) treatment of AAV vectors (e.g., scAAV.miniCMV.LIPA, scAAV.LP1.LIPA, scAAV.Cbh.LIPA, and ssAAV.Cbh.LIPA) in Lipa -/- mice.
  • AAV vectors e.g., scAAV.miniCMV.LIPA, scAAV.LP1.LIPA, scAAV.Cbh.LIPA, and ssAAV.Cbh.LIPA
  • Wild type (WT) and untreated Lipa -/- mice were compared to Lipa -/- treated with one of four AAVrh74 vectors (e.g., scAAV.miniCMV.LIPA, scAAV.LP1.LIPA, scAAV.Cbh.LIPA, and ssAAV.Cbh.LIPA) intravenously (IV) at 2 months of age at a dose of 4x10 13 vg/kg. All mice were analyzed at 6 months of age, after 4 months of treatment. As expected, LIPA enzyme activities in liver and serum, while increased, was not increased as dramatically as gene expression.
  • AAVrh74 vectors e.g., scAAV.miniCMV.LIPA, scAAV.LP1.LIPA, scAAV.Cbh.LIPA, and ssAAV.Cbh.LIPA
  • LP1 induced LIPA enzyme activity (by scAAV.LP1.LIPA vector) in Lipa -/- mouse spleen that was 16 times the normal wild type level (and 80 times the level found in untreated Lipa -/- mice), while the inclusion of the miniCMV promoter (by scAAV.miniCMV.LIPA vector) did not induce any increase in activity relative to untreated Lipa -/- mice.
  • LP1-treated kidney i.e., treated with scAAV.LP1.LIPA vector
  • had LAL activity that was 5.3 times wild type level
  • scAAV.miniCMV.LIPA was 0.1 times wild type.
  • LP1 liver specific LIPA gene therapy for the treatment of LALD was chosen for further experiments and as a strong candidate for future therapies.
  • mice were dosed at 2 months of age, a time when disease is already severe, or at 2 days of age (denoted as “P2”) which is prior to significant disease onset. All mice were assayed at 6 months of age, 4 months after treatment, a point at which LAL-D disease is quite severe. Table 3 [00120] Hepatosplenomegaly was investigated at 6 months of age. As shown in Figure 10, liver and spleen size increased dramatically in untreated Lipa -/- mice relative to wild type, such that the liver is about 4.8 times normal size by 6 months of age.
  • Treatment with AAV vectors having the LP1 promoter reduced the size of the liver and spleen, while both scAAV.Cbh.LIPA and ssAAV.Cbh.LIPA had less therapeutic impact. Treatment with the scAAV.LP1.LIPA was effective at all doses tested. [00121] Lipid content in the livers from the treated Lipa -/- mice was assayed by staining tissue section with oil O before and after injection. As shown in Figure 11, treatment with rscAAVrh74.LP1.LIPA reduced lipid content in the liver of Lipa -/- mice.
  • Figure 12 demonstrates that IV administration of 1x10 13 vg/kg of rscAAV.LP1.LIPA gene therapy increased survival of treated Lipa -/- mice. Untreated Lipa -/- mice do not survive beyond 305 days of age. Lipa -/- mice treated at 2 months of age (60 days) all survive to beyond this time point. [00123] AAV vector biodistribution and LIPA gene expression was measured in liver, spleen, intestine, and heart of the treated Lipa -/- mice using the methods described in Example 6 above. Lipa -/- mice were treated at 2 months or treated at postnatal day 2 (marked P2) and analyzed at 6 months of age.
  • AAV vectors having a promoter that is optimized for constitutive gene expression in all tissues was compared to LP1, a liver- specific promoter.
  • Cbh showed poor sustained gene expression in liver
  • LP1 showed very strong gene expression in liver.
  • Cbh also showsed lower AAV biodistribution in liver, suggesting clearance by immune factors.
  • LP1 only showed high levels of gene overexpression in liver (see Figure 13).
  • Treatment of the rscAAV.LP1.LIPA vector resulted in liver specific gene expression.
  • expression of LIPA driven by the LP1 promoter resulted in no detectable gene expression in the lymph node, lung, kidney, thymus, brain or skeletal muscles (gastrocnemius and quadriceps).
  • Drug Des Devel Ther 14 591-601. 2. Gomaraschi, M, Bonacina, F, and Norata, GD (2019). Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target. Trends Pharmacol Sci 40: 104-115. 3. Li, F, and Zhang, H (2019). Lysosomal Acid Lipase in Lipid Metabolism and Beyond. Arterioscler Thromb Vasc Biol 39: 850-856. 4. Aguisanda, F, Thorne, N, and Zheng, W (2017). Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development. Curr Chem Genom Transl Med 11: 1-18. 5.
  • rAAVrh74.MCK.GALGT2 Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates.
  • Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol 296: C476- 488. 23. Grieger, JC, and Samulski, RJ (2005).
  • Adeno-associated virus as a gene therapy vector vector development, production and clinical applications. Adv Biochem Eng Biotechnol 99: 119-145. 24. Rosas, LE, Grieves, JL, Zaraspe, K, La Perle, KM, Fu, H, and McCarty, DM (2012). Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther 20: 2098-2110. 25. Xiao, X, Li, J, and Samulski, RJ (1998). Production of high-titer recombinant adeno- associated virus vectors in the absence of helper adenovirus. J Virol 72: 2224-2232. 26.
  • Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther 19: 1359-1368. 27. Cunningham, SC, and Alexander, IE (2019). AAV-Mediated Gene Delivery to the Mouse Liver. Methods Mol Biol 1937: 213-219. 28. Palaschak, B, Herzog, RW, and Markusic, DM (2019). AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods. Methods Mol Biol 1950: 333- 360. 29.
  • Lysosomal acid lipase-deficient mice depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. J Lipid Res 42: 489-500.

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Abstract

L'invention concerne des vecteurs de thérapie génique, tels que le virus adéno-associé (AAV), conçus pour le traitement de troubles du déficit en lipase acide lysosomale (LAL-D), tels que la maladie de Wolman et la maladie de stockage d'ester de cholestéryle (CESD), la stéatose hépatique non alcoolique (NAFLD), ou la stéatohépatite non alcoolique (NASH). Les rAAV divulgués permettent d'adminstrer un ADNc de lipase A (LIPA) de type sauvage à un sujet en ayant besoin, ce qui aboutit à l'expression de la protéine de type sauvage.
PCT/US2024/032823 2023-06-07 2024-06-06 Thérapie génique pour le déficit en lipase acide lysosomale (lal-d) WO2024254319A1 (fr)

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