小柯机器人

法国巴黎萨克莱大学Federico Mingozzi和法国巴黎大学Sebastien Lacroix-Desmazes团队合作取得最新进展。他们揭示了IgG切割内肽酶可在腺相关病毒（AAV）中和抗体的情况下进行体内基因治疗。相关论文发表在2020年6月1日的《自然-医学》杂志上。

他们研究了免疫酶（IdeS）是否可以在基因治疗的背景下消除抗AAV抗体。他们显示在内肽酶治疗后体外有效裂解混合人IgG（静脉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。这些结果提供了克服基于AAV的基因治疗的现有抗体的潜在解决方案。

研究人员表示，AAV载体的中和抗体在人体中普遍存在，并阻断肝转导和载体的再给药。因此，它们代表了体内基因治疗的主要限制。本研究旨在克服抗AAV抗体的策略，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。IdeS是一种能够降解循环IgG的内肽酶，目前正在移植患者中对其进行检测。

附：英文原文

Title: IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies

Author: Christian Leborgne, Elena Barbon, Jeffrey M. Alexander, Hayley Hanby, Sandrine Delignat, Daniel M. Cohen, Fanny Collaud, Saghana Muraleetharan, Dan Lupo, Joseph Silverberg, Karen Huang, Laetitia van Wittengerghe, Batrice Marolleau, Adeline Miranda, Anna Fabiano, Victoria Daventure, Heena Beck, Xavier M. Anguela, Giuseppe Ronzitti, Sean M. Armour, Sebastien Lacroix-Desmazes, Federico Mingozzi

Issue&Volume: 2020-06-01

Abstract: Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans1,2, and block liver transduction3,4,5 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.

DOI: 10.1038/s41591-020-0911-7

Source: https://www.nature.com/articles/s41591-020-0911-7

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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