title: Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle.
abstract: Adeno-associated virus (AAV) is being developed as a vector capable of conferring long-term gene expression, which is useful in the treatment of chronic diseases. In most therapeutic applications, it is necessary to readminister the vector. This study characterizes the humoral immune response to AAV capsid proteins following intramuscular injection and its impact on vector readministration. Studies of mice and rhesus monkeys demonstrated the formation of neutralizing antibodies to AAV capsid proteins that persisted for over 1 year and then diminished, but this did not prevent the efficacy of vector readministration. More-detailed studies strongly suggested that the B-cell response was T cell dependent. This was further evaluated with a blocking antibody to human CD4, primatized for clinical trials, in a biologically compatible mouse in which the endogenous murine CD4 gene was functionally replaced with the human counterpart. Transient pharmacologic inhibition of CD4 T cells with CD4 antibody prevented an antivector response long after the effects of the CD4 antibody diminished; readministration of vector without diminution of gene expression was possible. Our studies suggest that truly durable transgene expression (i.e., prolonged genetic engraftment together with vector readministration) is possible with AAV in skeletal muscle, although it will be necessary to transiently inhibit CD4 T-cell function to avoid the activation of memory B cells.
authors.affiliation: Institute for Human Gene Therapy, Departments of Medicine and Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: N
authors.initials: N
authors.lastname: Chirmule
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.forename: A
authors.initials: A
authors.lastname: Truneh
authors.forename: M A
authors.initials: MA
authors.lastname: Schnell
authors.forename: J V
authors.initials: JV
authors.lastname: Hughes
authors.forename: P
authors.initials: P
authors.lastname: Zoltick
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000914:Antibodies, Viral / Q000097:blood; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002213:Capsid / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007132:Immunoglobulin Isotypes / Q000097:blood; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D010322:Parvoviridae Infections / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000906:Antibodies; D000914:Antibodies, Viral; D015704:CD4 Antigens; D007132:Immunoglobulin Isotypes; D011994:Recombinant Proteins