Sorbonne Université and INSERM U974, 105 boulevard de l'Hôpital, 75651, Paris, France.
Genethon, UMR_S951 Inserm, Univ Evry, Université Paris Saclay, EPHE, 1 bis rue de l'Internationale, 91000, Evry, France.
Nat Commun. 2018 Oct 5;9(1):4098. doi: 10.1038/s41467-018-06621-3.
Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8 T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25 T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.
腺相关病毒（AAV）载体介导的基因治疗是治疗系统性单基因疾病的一种很有前途的方法。然而，载体免疫原性是 AAV 载体基因转移的主要限制因素，特别是对于载体再给药。在这里，我们证明了包封雷帕霉素的合成疫苗颗粒（SVP[Rapa]）与 AAV 载体共同给药，可以防止抗衣壳体液和细胞介导的反应的诱导。这使得在小鼠和非人类灵长类动物中成功地进行了载体再给药。用 AAV 载体给药的 SVP[Rapa]以抗原选择性的方式减少 B 和 T 细胞的激活，抑制 CD8 T 细胞在肝脏中的浸润，并有效地阻断记忆 T 细胞反应。SVP[Rapa]的免疫调节作用可以通过脾细胞的过继转移从治疗过的小鼠转移到未处理的小鼠，并且可以通过耗尽 CD25 T 细胞来抑制，这表明调节性 T 细胞的作用。SVP[Rapa]与 AAV 载体共同给药是一种调节载体免疫原性并实现有效载体再给药的强大策略。
