Adeno-associated virus vector delivery of muscle specific micro-dystrophin to treat muscular dystrophy
AssigneeResearch Institute At Nationwide Children's Hospital
InventorsLouise Rodino-Klapac, Jerry R. Mendell
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Abstract
The invention provides gene therapy vectors, such as adeno-associated vims (AAV) vectors, expressing a miniaturized human micro-dystrophin gene and method of using these vectors to express micro-dystrophin in skeletal muscle s including diaphragm and cardiac muscle and to protect muscle fibers from injury, increase muscle strength and reduce and/or prevent fibrosis in subjects suffering from muscular dystrophy.
Claims82
A method of treating muscular dystrophy in a human subject in need thereof comprising the step of administering a recombinant adeno-virus associated (rAAV) rAAV.MHCK7.microdystrophin, wherein
- the rAAV is administered using a systemic route of administration and at a dose of about 5.0×1012 vg/kg to about 1.0×1015.
A method of expressing micro-dystrophin gene in a patient cell comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A method of decreasing serum CK levels in a patient in need thereof, the method comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A method of increasing micro-dystrophin positive fibers in a patient muscle tissue comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A method of increasing the expression of alpha-sarcoglycan in a patient in need thereof comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A method of increasing the expression of beta-sarcoglycan in a patient in need thereof comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A method of treating a patient with Duchenne muscular dystrophy or Becker muscular dystrophy comprising administering to the patient the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3 such that disease progression in the patient is delayed as measured by any of:
- the six minute walk test, time to rise, ascend 4 steps, ascend and descend 4 steps, North Star Ambulatory Assessment (NSAA), 10 meter timed test, 100 meter timed test, hand held dynamometry (HHD), Timed Up and Go, and/or Gross Motor Subtest Scaled (Bayley-III) score.
A composition for treating a muscular dystrophy in a human subject in need thereof, wherein the composition comprises a recombinant adeno-virus associated (rAAV) rAAV.MHCK7.microdystrophin, wherein the composition is formulated for a systemic route of administration and the dose of the rAAV is about 5×1012 vg/kg to about 1.0×1015 vg/kg.
A composition for treating Duchenne muscular dystrophy in a human subject in need thereof wherein the composition comprises a recombinant adeno-virus associated (rAAV) rAAV.MHCK7.microdystrophin, wherein
- the composition is formulated for administration by intravenous infusion over approximately one hour at a dose of about 2×1014 vg/kg, and
- wherein the rAAV comprises the AAVrh7.4.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
Use of a recombinant adeno-virus associated (rAAV) rAAV.MHCK7.microdystrophin for the preparation of a medicament for the treatment of a muscular dystrophy in a human subject in need thereof, wherein the medicament is formulated for a systemic route of administration and comprises a dose of rAAV of about 1×1014 vg/kg to about 4×1014 vg/kg.
Use of a recombinant adeno-virus associated (rAAV) rAAV.MHCK7.microdystrophin for the preparation of a medicament for treating Duchenne muscular dystrophy in a human subject in need thereof, wherein the medicament is formulated for administration by intravenous infusion over approximately one hour and comprises a dose of the rAAV of about 2×1014 vg/kg, and wherein the rAAV comprises the AAVrh74.MHCK7.micro-dystrophin construct nucleotide sequence of SEQ ID NO:
- 9 or of nucleotides 55-5021 of SEQ ID NO:
- 3.
A composition comprising
- a) the nucleotide sequence of SEQ ID NO:
- 3,
- b) the nucleotide sequence of SEQ ID NO:
- 8,
- c) the nucleotide sequence of SEQ ID NO:
- 9,
- d) rAAV comprising nucleotides 55-5021 of SEQ ID NO:
- 3,
- e) rAAV comprising the nucleic acid sequence of SEQ ID NO:
- 9,
- f) rAAV comprising nucleotides 1-4977 of SEQ ID NO:
- 8,
- g) rAAV particles comprising nucleotides 55-5021 of SEQ ID NO:
- 3,
- h) rAAV particles comprising the nucleic acid sequence of SEQ ID NO:
- 9, or
- i) rAAV particles comprising nucleotides 1-4977 of SEQ ID NO:
- 8.
Dependencies are inferred from the claim text.