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

Autor: Leborgne C; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Barbon E; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Alexander JM; Spark Therapeutics, Philadelphia, PA, USA., Hanby H; Spark Therapeutics, Philadelphia, PA, USA., Delignat S; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France.; Institut National de la Santé et de la Recherche Médicale, Paris, France., Cohen DM; Spark Therapeutics, Philadelphia, PA, USA., Collaud F; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Muraleetharan S; Spark Therapeutics, Philadelphia, PA, USA., Lupo D; Spark Therapeutics, Philadelphia, PA, USA., Silverberg J; Spark Therapeutics, Philadelphia, PA, USA., Huang K; Spark Therapeutics, Philadelphia, PA, USA., van Wittengerghe L; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Marolleau B; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Miranda A; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Fabiano A; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Daventure V; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France.; Institut National de la Santé et de la Recherche Médicale, Paris, France., Beck H; Spark Therapeutics, Philadelphia, PA, USA., Anguela XM; Spark Therapeutics, Philadelphia, PA, USA., Ronzitti G; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France., Armour SM; Spark Therapeutics, Philadelphia, PA, USA., Lacroix-Desmazes S; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France. sebastien.lacroix-desmazes@crc.jussieu.fr.; Institut National de la Santé et de la Recherche Médicale, Paris, France. sebastien.lacroix-desmazes@crc.jussieu.fr., Mingozzi F; Généthon INTEGRARE UMR-S951 (Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Université Paris Saclay), Evry, France. federico.mingozzi@sparktx.com.; Spark Therapeutics, Philadelphia, PA, USA. federico.mingozzi@sparktx.com.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2020 Jul; Vol. 26 (7), pp. 1096-1101. Date of Electronic Publication: 2020 Jun 01.
DOI: 10.1038/s41591-020-0911-7
Abstrakt: Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans 1,2 , and block liver transduction 3-5 and vector readministration 6 ; thus, they represent 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 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.
Databáze: MEDLINE
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