INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, Evry, France.
Spark Therapeutics, Philadelphia, PA, United States.
Front Immunol. 2020 Apr 17;11:670. doi: 10.3389/fimmu.2020.00670. eCollection 2020.
Recombinant adeno-associated virus (rAAV) vectors are one of the most promising gene delivery tools. Several features make rAAV vectors an ideal platform for gene transfer. However, the high homology with the parental wild-type virus, which often infects humans, poses limitations in terms of immune responses associated with this vector platform. Both humoral and cell-mediated immunity to wild-type AAV have been documented in healthy donors, and, at least in the case of anti-AAV antibodies, have been shown to have a potentially high impact on the outcome of gene transfer. While several factors can contribute to the overall immunogenicity of rAAV vectors, vector design and the total vector dose appear to be responsible of immune-mediated toxicities. While preclinical models have been less than ideal in predicting the outcome of gene transfer in humans, the current preclinical body of evidence clearly demonstrates that rAAV vectors can trigger both innate and adaptive immune responses. Data gathered from clinical trials offers key learnings on the immunogenicity of AAV vectors, highlighting challenges as well as the potential strategies that could help unlock the full therapeutic potential of gene transfer.
重组腺相关病毒（rAAV）载体是最有前途的基因传递工具之一。rAAV 载体有几个特点使其成为基因转移的理想平台。然而，与通常感染人类的亲本野生型病毒的高度同源性限制了该载体平台相关的免疫反应。在健康供体中已经记录了针对野生型 AAV 的体液和细胞介导免疫，并且至少在抗 AAV 抗体的情况下，已经表明其对基因转移的结果有潜在的重大影响。虽然有几个因素可以影响 rAAV 载体的整体免疫原性，但载体设计和总载体剂量似乎是免疫介导的毒性的原因。虽然临床前模型在预测人类基因转移的结果方面并不理想，但目前的临床前证据清楚地表明，rAAV 载体可以引发先天和适应性免疫反应。从临床试验中收集的数据提供了关于 AAV 载体免疫原性的关键知识，突出了挑战以及可能有助于充分发挥基因转移治疗潜力的潜在策略。
