Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme.

Journal Article (Journal Article)

Preexisting humoral immunity to recombinant adeno-associated virus (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression, are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.

Full Text

Duke Authors

Cited Authors

  • Elmore, ZC; Oh, DK; Simon, KE; Fanous, MM; Asokan, A

Published Date

  • September 17, 2020

Published In

Volume / Issue

  • 5 / 19

PubMed ID

  • 32941184

Pubmed Central ID

  • PMC7566709

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.139881

Language

  • eng

Conference Location

  • United States