title: Overcoming preexisting humoral immunity to AAV using capsid decoys.
abstract: Adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but cannot enter a target cell. Our work suggests that optimizing the ratio of full/empty capsids in the final formulation of vector, based on a patient's anti-AAV titers, will maximize the efficacy of gene transfer after systemic vector delivery.
authors.affiliation: Department of Pediatrics and Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. fmingozzi@genethon.fr
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Xavier M
authors.initials: XM
authors.lastname: Anguela
authors.forename: Giulia
authors.initials: G
authors.lastname: Pavani
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Davidson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: Mustafa
authors.initials: M
authors.lastname: Yazicioglu
authors.forename: Liron
authors.initials: L
authors.lastname: Elkouby
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hinderer
authors.forename: Armida
authors.initials: A
authors.lastname: Faella
authors.forename: Carolann
authors.initials: C
authors.lastname: Howard
authors.forename: Alex
authors.initials: A
authors.lastname: Tai
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Podsakoff
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: John Fraser
authors.initials: JF
authors.lastname: Wright
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002213:Capsid / Q000276:immunology*; D000229:Dependovirus / Q000276:immunology*; D018014:Gene Transfer Techniques; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009500:Neutralization Tests
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral