US2018135076A1PendingUtilityA1

Adeno-associated virus vector

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Assignee: KING S COLLEGE LONDONPriority: Feb 17, 2014Filed: Feb 17, 2015Published: May 17, 2018
Est. expiryFeb 17, 2034(~7.5 yrs left)· nominal 20-yr term from priority
Inventors:Ralph Michael Linden
A61P 27/02C12N 2750/14143A61K 48/0008C07K 14/005A61P 27/06C12N 15/86C12N 2750/14122A61P 25/00A61P 1/16C12N 2750/14142C12N 2750/14132A61K 48/00C12N 15/861
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Claims

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.

Claims

exact text as granted — not AI-modified
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  or  claim 2 , wherein the variant AAV2 capsid protein comprises one or more of the following residues: M457, A492, D499 and Y533. 
     
     
         4 . A recombinant AAV vector according to  claim 2  or  claim 3 , wherein the variant AAV2 capsid protein comprises one or more of the following amino acid substitutions with respect to a wild type AAV2 capsid protein: Q457M, S492A, E499D and F533Y. 
     
     
         5 . A recombinant AAV vector according to any of  claims 1  to  4 , 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 . A recombinant AAV vector according to  claim 5 , wherein the variant AAV2 capsid protein comprises one or more of one or more of the following residues: I125, A151, S162 and S205. 
     
     
         7 . A recombinant AAV vector according to  claim 5  or  claim 6 , wherein the variant AAV2 capsid protein comprises one or more of the following amino acid substitutions with respect to a wild type AAV2 capsid protein: V125I, V151A, A162S and T205S. 
     
     
         8 . A recombinant AAV vector according to any of  claims 1  to  7 , 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 . A recombinant AAV vector according to  claim 8 , wherein the variant AAV2 capsid protein comprises one or more of one or more of the following residues: S585 and T588. 
     
     
         10 . A recombinant AAV vector according to  claim 8  or  claim 9 , wherein the variant AAV2 capsid protein comprises one or more of the following amino acid substitutions with respect to a wild type AAV2 capsid protein: R585S and R588T. 
     
     
         11 . A recombinant AAV vector according to any of  claims 1  to  10 , 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 . A recombinant AAV vector according to  claim 11 , wherein the variant AAV2 capsid protein comprises one or more of one or more of the following residues: D546, G548, and S593. 
     
     
         13 . A recombinant AAV vector according to  claim 11  or  claim 12 , wherein the variant AAV2 capsid protein comprises one or more of the following amino acid substitutions with respect to a wild type AAV2 capsid protein: G546D, E548G and A593S. 
     
     
         14 . A recombinant AAV vector according to any of  claims 1  to  13 , 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  or  claim 16 , 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 any of  claims 15  to  17 , 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 . A recombinant AAV vector according to  claim 18 , wherein the variant AAV8 capsid protein comprises one or more of the following amino acid substitutions with respect to a wild type AAV8 capsid protein:
 (a) V125I, Q151A, K163S, A206S, T460M, T495A, N502D, F536Y, N549D, A551G, Q588S and/or G596S; and/or   (b) T591R.   
     
     
         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  or  claim 21 , 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 . A recombinant AAV vector according to any of  claims 1  to  14 , wherein the recombinant AAV vector exhibits increased transduction of a neuronal or retinal tissue compared to an AAV vector comprising a corresponding wild type AAV capsid protein. 
     
     
         26 . A recombinant AAV vector according to any of  claims 15  to  24 , wherein the recombinant AAV vector exhibits increased transduction of liver tissue compared to a corresponding wild type AAV capsid protein. 
     
     
         27 . A recombinant AAV vector according to any preceding claim, wherein the gene product comprises an interfering RNA or an aptamer. 
     
     
         28 . A recombinant AAV vector according to any of  claims 1  to  27 , wherein the gene product comprises a polypeptide. 
     
     
         29 . A recombinant AAV vector according to  claim 28 , wherein the gene product comprises a neuroprotective polypeptide, an anti-angiogenic polypeptide, or a polypeptide that enhances function of a neuronal or retinal cell. 
     
     
         30 . A recombinant AAV vector according to  claim 29 , wherein the gene product comprises glial derived neurotrophic factor, fibroblast growth factor, nerve growth factor, brain derived neurotrophic factor, rhodopsin, retinoschisin, RPE65 or peripherin. 
     
     
         31 . A pharmaceutical composition comprising:
 (a) a recombinant AAV vector according to any preceding claim; 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 any preceding claim. 
     
     
         33 . A method according to  claim 32 , wherein the tissue is selected from blood, bone marrow, muscle tissue, neuronal tissue, retinal tissue, pancreatic tissue, liver tissue, kidney tissue, lung tissue, intestinal tissue or heart tissue. 
     
     
         34 . A method according to  claim 33 , wherein the tissue is neuronal, retinal or liver tissue. 
     
     
         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 any preceding claim. 
     
     
         36 . A recombinant AAV vector or pharmaceutical composition according to any of  claims 1  to  31 , for use in treating a disorder in a subject. 
     
     
         37 . A method, recombinant AAV vector or pharmaceutical composition for use according to  claim 35  or  claim 36 , wherein the disorder is a neurological, ocular or hepatic disorder. 
     
     
         38 . A method, recombinant AAV vector or pharmaceutical composition for use according to  claim 37 , wherein the neurological disorder is a neurodegenerative disease. 
     
     
         39 . A method, recombinant AAV vector or pharmaceutical composition for use according to  claim 37 , wherein the ocular disorder is glaucoma, retinitis pigmentosa, macular degeneration, retinoschisis or diabetic retinopathy.

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