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重组腺相关病毒 (rAAV) 因具有在体内可以长期稳定表达转基因、安全性高等优点, 迅速成为基因治疗的首选载体之一。最近采用 rAAV 基因药物进行的血友病临床实验所暴露的细胞免疫毒性引起人们高度关注, 此问题能否顺利解决直接关系该类药物的发展前景。之后的研究发现针对 AAV 衣壳蛋白的 T 细胞免疫反应是毒性反应的原因。本文针对 rAAV 细胞免疫毒性的各种假说进行了分析, 总结了 AAV 衣壳蛋白抗原肽如何在靶细胞递呈并激活细胞毒性 T 淋巴细胞的研究结果, 并针对该免疫毒性的各关键环节提出了可能的解决方案, 包括免疫抑制、载体优化、提高纯度等, 期望有助于提高 rAAV 基因药物的临床安全性和有效性。
Recombinant adeno-associated virus (rAAV) is rapidly becoming one of the preferred vectors for gene therapy due to its long-term stable expression of the transgene in the body and its high safety. Recently, the immunological toxicity of cells exposed to hemophilia clinical trials using rAAV gene drugs has drawn great attention. Whether this problem can directly solve the development prospect of such drugs can be solved smoothly. Subsequent studies have found that T cell immune responses against AAV capsid proteins are responsible for the toxic effects. In this paper, we analyzed various hypotheses about the immunotoxicity of rAAV cells, summarized the research results on how AAV capsid antigen peptide presented and activated cytotoxic T lymphocytes in target cells, and put forward the key points of the immunotoxicity Possible solutions, including immunosuppression, vector optimization, improved purity, etc., are expected to help improve the clinical safety and efficacy of rAAV gene drugs.