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AssigneeThe Trustees of the University of Pennsylvania
InventorsJames M. Wilson, Christie L. Bell, Luc H. Vandenberghe
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A method of altering the targeting and/or cellular uptake efficiency of an adeno-associated virus (AAV) viral vector having a capsid containing an AAV9 cell surface binding domain is described. The method involves modifying a clade F cell surface receptor which comprises a glycan having a terminal sialic acid residue and a penultimate β-galactose residue. The modification may involve retargeting the vector by temporarily functionally ablate AAV9 binding in a subset of cells, thereby redirecting the vector to another subset of cells. Alternatively, the modification may involve increasing cellular update efficiency by treating the cells with a neuraminidase to expose cell surface β-galactose. Also provided are compositions containing the AAV9 vector and a neuraminidase. Also provided is a method for purifying AAV9 using β-galactose linked to solid support. Also provided are mutant vectors which have been modified to alter their targeting specificity, including mutant AAV9 in which the galactose binding domain is mutated and AAV in which an AAV9 galactose binding domain is engineered.
A method of increasing gene delivery of an adeno-associated virus (AAV) vector in a cell having a cell surface receptor which comprises a glycan having a terminal sialic acid residue and a subterminal β-galactose residue,
A method for isolating an adeno-associated virus (AAV) viral vector having a capsid from a clade F AAV, said method comprising:
A composition comprising a combination of (a) a neuraminidase, (b) an adeno-associated virus (AAV) vector having an AAV clade F capsid, wherein the capsid comprises a β-galactose binding domain, said vector further comprising a minigene having AAV inverted terminal repeats and a heterologous gene operably linked to regulatory sequences which direct its expression in a host cell, and (c) a pharmaceutically acceptable carrier.
A recombinant AAV vector having an AAV capsid with an engineered AAV9 cell binding domain, said AAV9 cell binding domain comprising amino acids Y446, N470, A472, V473, D271, N272, and W503 which forms a galactose binding domain with the positions based on the numbering of AAV9, SEQ ID NO:1, wherein one or more of these amino acids has replaced another amino acid which is native to the AAV capsid into which the AAV9 cell binding domain has been engineered.
A method of detargeting an AAV9 vector to airway epithelium while retaining the ability to transduce liver and heart, said method comprising replacing an AAV9 capsid in which a native AAV9 amino acid selected from the group consisting of:
Dependencies are inferred from the claim text.