Neutralizing antibodies (NAbs) to adeno-associated virus (AAV) vectors are highly prevalent in humans 1,2 , block liver transduction 3-5 and vector readministration 6 , thus representing a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied 7 , which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients 8 . Here we studied if IdeS can eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (IVIg) in vitro upon endopeptidase treatment. In mice passively immunized with IVIg, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer.The approach was scaled up to non-human primates, a natural host for wild type AAV.IdeS treatment prior to AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.
Key Points• Enveloped AAV vectors are able to transduce the liver highly efficiently, driving superior correction of hemophilia B in mice.• Enveloped AAVs are less susceptible to antibody-mediated neutralization, allowing for liver transduction in preimmunized animals. Exo-AAV vectors therefore represent a platform to improve the safety and efficacy of liver-directed gene transfer.
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