Gene therapy for the treatment of wilson's disease
AssigneeLogicBio Therapeutics, Inc.
InventorsShengwen Zhang, Jing Liao, Shaobin Wang
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Abstract
The present disclosure provides compositions and methods for gene therapy. Further, the present disclosure provides compositions and methods for treatment of Wilson's Disease through novel gene therapy mechanisms. Wherein a composition of a closed circular cDNA integrating gene therapy construct, the gene therapy construct comprising, from 5′ to 3′, a polynucleotide sequence is disclosed.
Claims33
A composition comprising:
- a closed circular cDNA integrating gene therapy construct comprising, from 5′ to 3′, a polynucleotide sequence encoding (a) a 5′ homology arm between 0.4 kb and 0.8 kb in length, (b) a P2A coding sequence encoding a P2A peptide, (c) a therapeutic payload, and (d) a 3′ homology arm between 0.4 kb and 0.8 kb in length, wherein:
- the therapeutic payload comprises a transgene sequence encoding ATP7B or a variant thereof;
- and
- the homology arm sequences promote integration of the construct at an endogenous albumin target site such that the albumin locus can result in the simultaneous production of albumin-2A and the transgene as separate proteins.
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The composition of claim, wherein;
- (a) the P2A coding sequence comprises the nucleotide sequence of SEQ ID NO:
- 16 or SEQ ID NO:
- 17;
- and/or
- (b) the P2A coding sequence encodes a peptide comprising the amino acid sequence of SEQ ID NO:
- 18.
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A liver-targeted, recombinant AAV vector for treating Wilson's Disease and encoding the therapeutic transgene ATP7B, the viral vector comprising a closed, circular cDNA polynucleotide sequence comprising
- an ATP7B polynucleotide sequence encoding a functional ATP7B therapeutic transgene comprising the nucleotide sequence of SEQ ID NO:15, preceded by a 2A-peptide sequence encoding a 2A-peptide comprising the amino acid sequence of SEQ ID NO:
- 18;
- the ATP7B polynucleotide sequence and 2A-peptide sequence together flanked by a 3′ homology arm comprising the nucleotide sequence of SEQ ID NO:
- 9, SEQ ID NO:
- 10, or SEQ ID NO:
- 11;
- and a 5′ homology arm comprising the nucleotide sequence of SEQ ID NO:6, SEQ ID NO:
- 7, or SEQ ID NO:8.
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A method of treating Wilson's Disease comprising administering to a subject in need thereof a therapeutically effective dose of a liver-targeted, recombinant AAV vector encoding the therapeutic transgene ATP7B, the viral vector comprising a cDNA polynucleotide sequence comprising
- an ATP7B polynucleotide sequence encoding a functional ATP7B therapeutic transgene comprising the nucleotide sequence of SEQ ID NO:15, preceded by a 2A-peptide sequence encoding a 2A-peptide comprising the amino acid sequence of SEQ ID NO:
- 18;
- the ATP7B polynucleotide sequence and 2A-peptide sequence together flanked by a 3′ homology arm comprising the nucleotide sequence of SEQ ID NO:
- 9, SEQ ID NO:
- 10, or SEQ ID NO:
- 11;
- and a 5′ homology arm comprising the nucleotide sequence of SEQ ID NO:6, SEQ ID NO:
- 7, or SEQ ID NO:8.
A method of reducing the level of non-ceruloplasmin-bound copper in a subject in need thereof, the method comprising administering to a subject in need thereof a liver-targeted, recombinant AAV vector encoding the therapeutic transgene ATP7B in an amount effective to reduce the level of non-ceruloplasmin-bound copper in the subject, the liver-targeted, recombinant AAV vector comprising a cDNA polynucleotide sequence expressing a functional therapeutic ATP7B transgene preceded by a 2A-peptide coding sequence and flanked by 0.4 kb and 0.8 kb gene homology arms spanning the albumin stop codon, wherein the homology arm sequences promote integration of the construct at an endogenous albumin target site, such that the albumin locus can result in the simultaneous production of albumin-2A and the ATP7B transgene as separate proteins.
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Dependencies are inferred from the claim text.