Adeno-associated virus vector

Abstract

Disclosed herein is a recombinant adeno-associated virus (AAV) vector comprising (a) a variant AAV2 capsid protein, wherein the variant AAV2 capsid protein comprises at least four amino acid substitutions with respect to a wild type AAV2 capsid protein; wherein the at least four amino acid substitutions are present at the following positions in an AAV2 capsid protein sequence: 457, 492, 499 and 533; and (b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.

1 . A recombinant adeno-associated virus (AAV) vector comprising:
 (a) a variant AAV2 capsid protein, wherein the variant AAV2 capsid protein comprises at least four amino acid substitutions with respect to a wild type AAV2 capsid protein; wherein the at least four amino acid substitutions are present at the following positions in an AAV2 capsid protein sequence: 457, 492, 499 and 533; and   (b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         2 . A recombinant AAV vector according to  claim 1 , wherein (i) the variant AAV capsid protein comprises a sequence of SEQ ID NO:2, or a sequence having at least 95% sequence identity thereto; and/or (ii) the wild type AAV capsid protein comprises a sequence of SEQ ID NO:1. 
     
     
         3 . A recombinant AAV vector according to  claim 1 , wherein the variant AAV2 capsid protein comprises one or more of the following residues: M457, A492, D499 and Y533. 
     
     
         4 . (canceled) 
     
     
         5 . A recombinant AAV vector according  claim 1 , wherein the variant AAV2 capsid protein further comprises one or more amino acid substitutions with respect to the wild type AAV capsid protein at the following positions in the AAV2 capsid protein sequence: 125, 151, 162 and 205. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . A recombinant AAV vector according to  claim 1 , wherein the variant AAV2 capsid protein further comprises one or more amino acid substitutions with respect to the wild type AAV capsid protein at the following positions in the AAV2 capsid protein sequence: 585 and 588. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A recombinant AAV vector according to  claim 1 , wherein the variant AAV2 capsid protein further comprises one or more amino acid substitutions with respect to the wild type AAV capsid protein at the following positions in the AAV2 capsid protein sequence: 546, 548 and 593. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . A recombinant AAV vector according to  claim 1 , wherein the variant AAV2 capsid protein comprises the residue N312. 
     
     
         15 . A recombinant adeno-associated virus (AAV) vector comprising:
 (a) a variant AAV8 capsid protein, wherein the variant AAV8 capsid protein comprises an amino acid substitution with respect to a wild type AAV8 capsid protein at position 315 in an AAV8 capsid protein sequence; and   (b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         16 . A recombinant AAV vector according to  claim 15 , wherein (i) the variant AAV capsid protein comprises a sequence having at least 95% sequence identity to SEQ ID NO:6; and/or (ii) the wild type AAV capsid protein comprises a sequence of SEQ ID NO:6. 
     
     
         17 . A recombinant AAV vector according to  claim 15 , wherein the variant AAV8 capsid protein comprises the amino acid substitution S315N with respect to a wild type AAV8 capsid protein. 
     
     
         18 . A recombinant AAV vector according to  claim 15 , further comprising one or more amino acid substitution present at one or more of the following positions in the AAV8 capsid protein sequence: 125, 151, 163, 206, 460, 495, 502, 536, 549, 551, 588, 591 and/or 596. 
     
     
         19 . (canceled) 
     
     
         20 . A recombinant adeno-associated virus (AAV) vector comprising:
 (a) a variant AAV3B capsid protein, wherein the variant AAV3B capsid protein comprises an amino acid substitution with respect to a wild type AAV3B capsid protein at position 312 in an AAV3B capsid protein sequence; and   (b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         21 . A recombinant AAV vector according to  claim 20 , wherein (i) the variant AAV3B capsid protein comprises a sequence having at least 95% sequence identity to SEQ ID NO:11; and/or (ii) the wild type AAV capsid protein comprises a sequence of SEQ ID NO:11. 
     
     
         22 . A recombinant AAV vector according to  claim 20 , wherein the variant AAV3B capsid protein comprises the amino acid substitution S312N with respect to a wild type AAV3B capsid protein. 
     
     
         23 . A recombinant adeno-associated virus (AAV) vector comprising:
 (a) a variant AAV-LK03 capsid protein, wherein the variant AAV-LK03 capsid protein comprises an amino acid substitution at position 312 with respect to a AAV-LK03 capsid protein sequence as defined in SEQ ID NO:12; and   (b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         24 . A recombinant AAV vector according to  claim 23 , wherein the variant AAV-LK03 capsid protein comprises a sequence having at least 95% sequence identity to SEQ ID NO:12. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . A recombinant AAV vector according to  claim 1 , wherein the gene product comprises an interfering RNA, an aptamer, a polypeptide, a neuroprotective polypeptide, an anti-angiogenic polypeptide, a polypeptide that enhances function of a neuronal or retinal cell, glial derived neurotrophic factor, fibroblast growth factor, nerve growth factor, brain derived neurotrophic factor, rhodopsin, retinoschisin, RPE65 or peripherin. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising:
 (a) a recombinant AAV vector according to  claim 1 ; and   (b) a pharmaceutically acceptable excipient.   
     
     
         32 . A method for delivering a gene product to a tissue in a subject, the method comprising administering to the subject a recombinant AAV vector or pharmaceutical composition according to  claim 1 . 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . A method for treating a disorder in a subject, the method comprising administering to the subject a recombinant AAV vector or pharmaceutical composition according to  claim 1 . 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled)