Systemic delivery of adeno-associated virus vector expressing gamma-sarcoglycan and the treatment of muscular dystrophy
Inventors
Rodino-Klapac, Louise • POZSGAI, Eric
Assignees
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Publication Number
US-11925675-B2
Publication Date
2024-03-12
Expiration Date
Abstract
Described herein are methods of treating muscular dystrophy comprising administering to a subject a recombinant AAV (rAAV) scAAVrh74.MHCK7.hSGCG vector, methods of expressing gamma-sarcoglycan gene in a patient, pharmaceutical compositions comprising the rAAV scAAVrh74.MHCK7.hSGCG for usage in such methods, the doses and the ranges thereof for such methods, and methods of generating and producing the rAAV scAAVrh74.MHCK7.hSGCG.
Core Innovation
The invention relates to gene therapy for limb-girdle muscular dystrophy type 2C (LGMD2C) using a recombinant adeno-associated virus (rAAV) vector scAAVrh74.MHCK7.hSGCG. The approach administers the rAAV using a systemic route of administration, including an intravenous infusion embodiment, to deliver a nucleotide sequence for human γ-sarcoglycan (hSGCG). The described vector is linked to increased γ-sarcoglycan expression and localization in treated muscle.
The problem addressed is muscular dystrophy in a subject in need thereof, specifically LGMD2C, for which administration of an rAAV expressing γ-sarcoglycan is intended to improve muscular dystrophy outcomes. The partial content states that systemic administration at specified dose levels results in increased γ-sarcoglycan gene/protein expression and increased γ-sarcoglycan-positive fibers. The treatment is further associated with decreased serum creatine kinase (CK), improved muscle pathology including reduced fibrosis and reduced central nucleation, and improved muscle function using functional readouts.
The document further describes related embodiments that aim to increase α-sarcoglycan (SGCA) and β-sarcoglycan (SGCB) expression and/or localization, along with pharmaceutical compositions that include buffer/ionic strength/surfactant elements. The partial content also describes characterization elements including vector/plasmid sequence identity to provided sequence identifiers (SEQ ID NOs) and supporting preclinical findings in a mouse model, including biodistribution, immunofluorescence, Western blot, histology, and serum chemistry readouts.
Claims Coverage
The partial content provides one independent claim (clm-00001) directed to a method of treating muscular dystrophy by systemic administration of a specific recombinant AAV at defined doses with a specified sequence identity requirement. Main inventive features are captured below based on the independent claim and the explicitly described dependent refinements.
Treating muscular dystrophy with scAAVrh74.MHCK7.hSGCG systemic delivery
Administering a recombinant adeno-associated virus (rAAV) scAAVrh74.MHCK7.hSGCG to a subject in need thereof as treatment for muscular dystrophy, wherein the rAAV is administered using a systemic route of administration.
Linearized-plasmid dose levels for scAAVrh74.MHCK7.hSGCG
Administering the rAAV at a dose of about 4.63×10^12 vg/kg, about 1.85×10^13 vg/kg, or about 7.41×10^13 vg/kg based on a linearized plasmid as the quantitation standard.
Permitted nucleotide sequence identity to SEQ ID NO: 7 or SEQ ID NO: 10
Using an rAAV comprising a nucleotide sequence that is identical to SEQ ID NO: 7 or SEQ ID NO: 10.
Intravenous administration of the systemic treatment
Carrying out the method by administering the rAAV via an intravenous route.
Specific permitted nucleotide sequence variant SEQ ID NO: 10
Practicing the method using an rAAV that contains the nucleotide sequence of SEQ ID NO: 10.
Overall, the claim coverage centers on systemic delivery of scAAVrh74.MHCK7.hSGCG to treat muscular dystrophy, with doses defined using a linearized-plasmid quantitation standard, and with the rAAV nucleotide sequence required to be identical to SEQ ID NO: 7 or SEQ ID NO: 10. Dependent elements explicitly narrow the route to intravenous and specify a permitted sequence variant (SEQ ID NO: 10), and additionally (as described in the partial claim set) include quantified efficacy and biomarker endpoints.
Stated Advantages
Increases γ-sarcoglycan gene/protein expression.
Increases γ-sarcoglycan-positive fibers.
Decreases serum creatine kinase (CK).
Improves muscle pathology, including reduced fibrosis and/or reduced central nucleation.
Improves muscle function, including motor function measures such as timed walk/NSAD.
Reduces serum ALT and serum AST (as stated among discussed biomarkers).
Documented Applications
Gene therapy for limb-girdle muscular dystrophy type 2C (LGMD2C) using recombinant AAV scAAVrh74.MHCK7.hSGCG delivered by systemic administration (including intravenous infusion).
Treatment of muscular dystrophy in a subject in need thereof using the described rAAV and specified dose/sequence requirements.
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