Treatment of dystrophinopathies with microdystrophin gene therapy constructs
AssigneeREGENXBIO Inc.
InventorsChunping Qiao, Devin McDougald, Ye Liu, Olivier Danos
Life of this patent
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Abstract
Provided are gene constructs that encode a microdystrophin protein for use in gene therapy. The microdystrophin gene constructs and expression cassettes were engineered for improved therapy with respect to efficacy, potency and safety to the subject when expressed by a viral vector in muscle cells and/or CNS cells.
Claims46
A method of treating a dystrophinopathy in a human subject in need thereof, the method comprising:
- administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) particle, wherein the rAAV particle comprises a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising an amino acid sequence at least 97% identical to the amino acid sequence of SEQ ID NO:
- 79, or the reverse complement of the nucleotide sequence, wherein the microdystrophin protein comprises an H3 domain and a C-terminal (CT) domain, wherein the CT domain comprises an α1-syntrophin binding site, and b) a capsid comprising a capsid protein,
- wherein the administration results in delivery of a microdystrophin protein to the muscle of the subject.
A method of treating a dystrophinopathy in a human subject in need thereof, the method comprising:
- administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an rAAV particle, wherein the rAAV particle comprises a) a nucleic acid comprising a nucleotide sequence encoding a microdystrophin protein comprising an amino acid sequence at least 97% identical to the amino acid sequence of SEQ ID NO:
- 1, or the reverse complement of the nucleotide sequence, wherein the microdystrophin protein comprises an H3 domain and a C-terminal (CT) domain, wherein the CT domain comprises an α1-syntrophin binding site, and b) a capsid comprising a capsid protein,
- wherein the administration results in delivery of a microdystrophin protein to the muscle of the subject.
A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle comprising the nucleic acid encoding the microdystrophin protein,
- wherein the microdystrophin protein comprises an amino acid sequence at least 97% identical to the amino acid sequence of SEQ ID NO:
- 79, wherein the microdystrophin protein comprises an H3 domain and a C-terminal (CT) domain, wherein the CT domain comprises an α1-syntrophin binding site, and wherein the nucleic acid encoding the microdystrophin protein is delivered to the cell.
A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle comprising the nucleic acid encoding the microdystrophin protein,
- wherein the microdystrophin protein comprises an amino acid sequence at least 97% identical to the amino acid sequence of SEQ ID NO:
- 1, wherein the microdystrophin protein comprises an H3 domain and a C-terminal (CT) domain, wherein the CT domain comprises an α1-syntrophin binding site, —and wherein the nucleic acid encoding the microdystrophin protein is delivered to the cell.
A method of treating a dystrophinopathy in a human subject in need thereof, said method comprising:
- administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) particle, wherein the rAAV particle comprises
- a) a nucleic acid comprising i) a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO:
- 1, and ii) a transcription regulatory element comprising the nucleotide sequence of SEQ ID NO:
- 39;
- and
- b) a capsid comprising a capsid protein,
- wherein said administration results in delivery of a microdystrophin protein to the muscle of said subject.
A method of treating a dystrophinopathy in a human subject in need thereof, said method comprising:
- administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) particle, wherein the rAAV particle comprises a) a nucleic acid comprising from 5′ to 3′:
- (i) a first AAV2 ITR comprising the nucleotide sequence of SEQ ID NO:
- 73, (ii) a SPc5-12 promoter comprising the nucleotide sequence of SEQ ID NO:
- 39, (iii) a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO:
- 1, (iv) a polyadenylation nucleotide sequence of SEQ ID NO:
- 42, and (v) a second AAV2 ITR comprising the nucleotide sequence of SEQ ID NO:
- 74;
- and b) a capsid comprising a capsid protein,
- wherein said administration results in delivery of a microdystrophin protein to the muscle of said subject.
A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle comprising the nucleic acid encoding the microdystrophin protein and an SPc5-12 promoter comprising the nucleotide sequence of SEQ ID NO:
- 39,
- wherein the microdystrophin protein comprises the amino acid sequence of SEQ ID NO:
- 1, and
- wherein the nucleic acid encoding the microdystrophin protein and the SPc5-12 promoter is delivered to the cell.
A method of delivering a nucleic acid encoding a microdystrophin protein to a cell, the method comprising contacting the cell with an rAAV particle wherein the rAAV particle comprises a) the nucleic acid comprising from 5′ to 3′:
- (i) a first AAV2 ITR comprising the nucleotide sequence of SEQ ID NO:
- 73, (ii) a SPc5-12 promoter comprising the nucleotide sequence of SEQ ID NO:
- 39, (iii) a nucleotide sequence encoding a microdystrophin protein comprising the amino acid sequence of SEQ ID NO:
- 1, (iv) a polyadenylation nucleotide sequence of SEQ ID NO:
- 42, and (v) a second AAV2 ITR comprising the nucleotide sequence of SEQ ID NO:
- 74 and b) a capsid comprising a capsid protein, wherein the nucleic acid encoding the microdystrophin protein is delivered to the cell.
Dependencies are inferred from the claim text.