Methods and compositions for dual glycan binding aav2.5 vector

Abstract

Disclosed herein are methods and compositions comprising an adeno-associated virus 2.5 (AAV2.5) capsid protein, comprising one or more amino acids substitutions, (e.g., which does not contain a substitution at the position corresponding to amino acid 267 of AAV2.5, or does not contain a serine at the position corresponding to amino acid 267 of AAV2.5) wherein the substitutions introduce a new glycan binding site into the AAV capsid protein.

That which is claimed is: 
     
         1 . A method of treating a disease or disorder in a subject in need thereof, comprising introducing a therapeutic nucleic acid into a cell of the subject by administering to the subject an AAV vector comprising:
 a) an AAV capsid protein that comprises an AAV2.5 VP1 capsid protein, further comprising amino acid substitutions that introduce a galactose-binding site, wherein the amino acid substitutions comprise Q465V, A468P, D470N, I471M, R472A, D473V, S475G, Y501F, and S502A, wherein the amino acid sequence is SEQ ID NO:2; and   b) a therapeutic nucleic acid comprising at least one terminal repeat sequence,   
       wherein the nucleic acid is encapsidated by the AAV capsid, under conditions whereby the therapeutic nucleic acid is expressed in the cell of the subject. 
     
     
         2 . The method of  claim 1 , wherein the AAV vector is formulated in a pharmaceutically acceptable carrier. 
     
     
         3 . The method of  claim 1 , wherein the AAV capsid protein further comprises an amino acid substitution at the position corresponding to amino acid 267 of AAV2.5 which is not a serine. 
     
     
         4 . The method of  claim 1 , wherein the capsid protein confers dual glycan binding ability to an AAV vector. 
     
     
         5 . The method of  claim 1 , wherein the subject is a human. 
     
     
         6 . The method of  claim 5 , wherein the subject is a child. 
     
     
         7 . The method of  claim 6 , wherein the child is an infant. 
     
     
         8 . The method of  claim 1 , wherein the subject is in utero. 
     
     
         9 . The method of  claim 1 , wherein the subject has or is at risk for a central nervous system (CNS) disease or disorder. 
     
     
         10 . The method of  claim 1 , wherein the subject has or is at risk for a congenital neurodegenerative disorder. 
     
     
         11 . The method of  claim 1 , wherein the subject has or is at risk for adult-onset autosomal dominant leukodystrophy (ADLD), Aicardi-Goutieres syndrome, Alexander disease, CADASIL, Canavan disease, CARASIL, cerebrotendinous xanthomatosis childhood ataxia and cerebral hypomyelination (CACH)/vanishing white matter disease (VWMD), Fabry disease, fucosidosis. GM1 gangliosidosis, Krabbe disease, L-2-hydroxyglutaric aciduria megalencephalic leukoencephalopathy with subcortical cysts, metachromatic leukodystrophy, multiple sulfatase deficiency, Pelizaeus-Merzbacher disease, Pol III-Related Leukodystrophies, Refsum disease, salla disease (free sialic acid storage disease), Sjogren-Larsson syndrome, X-linked adrenoleukodystrophy, Zellweger syndrome spectrum disorders, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type II, Mucopolysaccharidosis Type III, Mucopolysaccharidosis Type IV, Mucopolysaccharidosis Type V, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis Type VII, Mucopolysaccharidosis Type IX and any combination thereof. 
     
     
         12 . The method of  claim 1 , wherein the subject has or is at risk of having pain associated with a disease or disorder. 
     
     
         13 . The method of  claim 1 , wherein the virus vector or composition is administered to the subject via an enteral, parenteral, intrathecal, intracisternal, intracerebral, intraventricular, intranasal, intra-aural, intra-ocular, peri-ocular, intrarectal, intramuscular, intraperitoneal, intravenous, oral, sublingual, subcutaneous and/or transdermal route, to thereby contact the cell. 
     
     
         14 . The method of  claim 1 , wherein the virus vector or composition is administered to the subject intracranially and/or intraspinally, to thereby contact the cell. 
     
     
         15 . The method of  claim 1 , wherein the cell is in neural tissue. 
     
     
         16 . The method of  claim 15 , wherein the cell is a neuron or a glial cell. 
     
     
         17 . The method of  claim 16 , wherein the glial cell is an astrocyte. 
     
     
         18 . The method of  claim 15 , wherein the AAV vector has enhanced transduction of neural tissue as compared to an AAV1, AAV2, AAV9, or AAV2.5 virus vector. 
     
     
         19 . The method of  claim 15 , wherein the subject has a reduced immunologic profile when contacted with the AAV vector as compared to when contacted with an AAV1, AAV2, AAV9, or AAV2.5 virus vector.