Therapeutic methods based on tyrosine-substituted, capsid-modified rAAV vectors
AssigneeUniversity of Florida Research Foundation, Inc.
InventorsLi Zhong, Sergei Zolotukhin, Lakshmanan Govindasamy, Mavis Agbandje-McKenna, Arun Srivastava
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Abstract
Disclosed are tyrosine-modified rAAV vectors, as well as infectious virions, compositions, and pharmaceutical formulations that comprise them. Also disclosed are methods of preparing and methods for using the disclosed tyrosine-phosphorylated capsid protein mutant rAAV vectors in a variety of diagnostic and therapeutic applications including in vivo and ex vivo gene therapy, and large-scale production of rAAV vectors.
Claims20
A method for administering a therapeutic or a diagnostic agent to a mammal in need thereof, the method comprising:
- providing to at least a first cell, tissue or organ of the mammal, a composition comprising a recombinant adeno-associated viral (rAAV) vector that encodes a modified capsid protein, wherein the modified capsid protein comprises at least a first non-tyrosine amino acid at a position that corresponds to a surface-exposed tyrosine residue selected from the group consisting of Tyr252, Tyr272, Tyr275, Tyr281, Tyr508, Tyr612, Tyr704, Tyr720, Tyr730, and Tyr673in the wild-type AAV2 capsid protein, and further wherein the transduction efficiency of a virion comprising the modified capsid protein is higher than that of a virion comprising a corresponding, unmodified, wild-type capsid protein.
A method of providing a therapeutic peptide, polypeptide, or RNA to a mammal in need thereof, the method comprising:
- introducing into a selected population of cells of the mammal an effective amount of a recombinant adeno-associated viral (rAAV) vector that encodes a mutated capsid protein in which at least one native, surface-exposed-tyrosine residue is substituted by at least one non-tyrosine residue at an amino acid corresponding to Tyr252, Tyr272, Tyr275, Tyr281, Tyr508, Tyr612, Tyr704, Tyr720, Tyr730, or Tyr673 of a wild-type AAV2capsid protein;
- wherein the vector comprises a nucleic acid segment that encodes the therapeutic peptide, polypeptide, or RNA, operably linked to at least one promoter that expresses the nucleic acid segment in one or more cells of the selected population.
A method of treating or ameliorating one or more symptoms of a disease, a disorder, a dysfunction, an injury, or trauma in a mammal, comprising administering to the mammal an effective amount of a recombinant adeno-associated viral (rAAV) vector that encodes a mutated capsid protein in which at least one native, surface-exposed-tyrosine residue is substituted by at least one non-tyrosine residue at an amino acid corresponding to Tyr252, Tyr272, Tyr275, Tyr281, Tyr508, Tyr612, Tyr704, Tyr720, Tyr730, or Tyr673 of a wild-type AAV2 capsid protein;
- wherein the vector comprises a nucleic acid segment that encodes the therapeutic peptide, polypeptide, or RNA, operably linked to at least one promoter that expresses the nucleic acid segment in one or more cells of the selected population.
Dependencies are inferred from the claim text.