Aav capsids for improved heart transduction and detargeting of liver
AssigneeThe Trustees of the University of Pennsylvania
InventorsJacob Hoffman, Joshua Joyner Sims
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Abstract
Provided herein are novel AAV capsids and recombinant AAV vectors comprising the same. In certain embodiment, vectors comprising a novel AAV capsid show improved transduction of cardiac tissue and/or reduced targeting of liver tissue compared to a prior art AAV capsid.
Claims19
A recombinant adeno-associated virus (rAAV) having an AAV clade F capsid comprising a mutant galactose binding site,
- wherein the mutant galactose binding site comprises (a) any amino acid residue (X) at position 446 (Y446X), (b) an arginine at position 470 (N470R), and (c) a histidine at position 503 (W503H) when residue positions are determined using the residue numbers of SEQ ID NO:
- 10 as a reference, and
- a vector genome comprising a 5′ inverted terminal repeat (ITR) sequence, a coding sequence for a gene product, regulatory sequences operably linked to the coding sequence that direct expression of the gene product, and a 3′ ITR sequence.
A method for generating an a rAAV comprising a mutant capsid derived from a parental AAV capsid having liver specificity, the method comprising culturing a packaging host cell comprising:
- (a) a nucleic acid sequence encoding a mutant AAV Clade F capsid operably linked to regulatory control sequences that direct its expression in the packaging host cell, wherein the encoded capsid protein comprises (i) any amino acid residue (X) at position 446 (Y446X), (ii) an arginine at position 470 (N470R), and (iii) a histidine at position 503 (W503H), where the amino acid residue positions are determined using the residue numbers of SEQ ID NO:
- 10 as a reference,
- (b) a nucleic acid molecule comprising a vector genome comprising a 5′ inverted terminal repeat (ITR) sequence, a coding sequence for a gene product, regulatory sequences operably linked to the coding sequence that direct expression of the gene product, and a 3′ ITR sequence;
- and
- (c) helper functions necessary for packaging the vector genome of (b) into the mutant Clade F capsid.
A nucleic acid comprising a sequence encoding a mutant AAV Clade F VP1 protein having a mutant galactose binding pocket which comprises (a) any amino acid residue (X) at position 446 (Y446X), (b) arginine at position 470 (N470R), and (c) histidine at position 503 (W503H), where the amino acid residue positions are determined using the residue numbers of SEQ ID NO:
- 10 as a reference, the VP1 protein coding sequence being operably linked to expression control sequences which direct its expression in a packaging host cell.
Dependencies are inferred from the claim text.