Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans^1,2, and block liver transduction^3,4,5 and vector readministration⁶; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied⁷, 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 patients⁸. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before 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.

腺相关病毒（AAV）载体的中和抗体在人^1,2中高度流行，并阻断肝转导^3、4、5和载体重新给药⁶；因此，它们代表了体内基因治疗的主要限制。正在研究旨在克服抗AAV抗体的策略⁷，这些策略通常涉及免疫抑制作用，并且不能有效去除已有的抗体。免疫酶（IdeS）是一种能够降解循环IgG的内肽酶，目前正在移植患者中进行测试⁸。在这里，我们研究了IdeS是否可以在基因治疗的背景下消除抗AAV抗体。我们显示在内肽酶治疗后体外有效裂解合并的人IgG（静脉注射Ig）。在用静脉注射Ig被动免疫的小鼠中，IdeS给药减少了抗AAV抗体并实现了有效的肝基因转移。该方法已扩大到非人类灵长类动物，这是野生型AAV的天然宿主。AAV载体输注前的IdeS治疗是安全的，即使在载体重新给药的情况下，也能增强肝转导。最后，Ides降低了体外人血浆样品（包括来自前瞻性基因治疗试验参与者的血浆）的抗AAV抗体水平。这些结果为克服基于AAV的基因治疗的现有抗体提供了潜在的解决方案。