Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 386 Plantation Street, Worcester, MA, 01605, USA.
Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA, USA.
BioDrugs. 2023 May;37(3):311-329. doi: 10.1007/s40259-023-00585-7. Epub 2023 Mar 2.
Recombinant adeno-associated viruses (AAVs) have emerged as promising gene delivery vehicles resulting in three US Food and Drug Administration (FDA) and one European Medicines Agency (EMA)-approved AAV-based gene therapies. Despite being a leading platform for therapeutic gene transfer in several clinical trials, host immune responses against the AAV vector and transgene have hampered their widespread application. Multiple factors, including vector design, dose, and route of administration, contribute to the overall immunogenicity of AAVs. The immune responses against the AAV capsid and transgene involve an initial innate sensing. The innate immune response subsequently triggers an adaptive immune response to elicit a robust and specific response against the AAV vector. AAV gene therapy clinical trials and preclinical studies provide important information about the immune-mediated toxicities associated with AAV, yet studies suggest preclinical models fail to precisely predict the outcome of gene delivery in humans. This review discusses the contribution of the innate and adaptive immune response against AAVs, highlighting the challenges and potential strategies to mitigate these responses, thereby enhancing the therapeutic potential of AAV gene therapy.
重组腺相关病毒（AAV）已成为有前途的基因传递载体，促成了三种获得美国食品和药物管理局（FDA）和一种欧洲药品管理局（EMA）批准的基于 AAV 的基因疗法。尽管 AAV 是多种临床试验中治疗性基因转移的主要平台，但机体对 AAV 载体和转基因的免疫反应阻碍了其广泛应用。多种因素，包括载体设计、剂量和给药途径，都对 AAV 的总体免疫原性有影响。针对 AAV 衣壳和转基因的免疫反应涉及初始的先天感应。随后，先天免疫反应引发适应性免疫反应，引发针对 AAV 载体的强烈和特异性反应。AAV 基因治疗临床试验和临床前研究提供了有关与 AAV 相关的免疫介导毒性的重要信息，但研究表明，临床前模型未能准确预测基因传递在人类中的结果。本文讨论了针对 AAV 的先天和适应性免疫反应的贡献，强调了减轻这些反应的挑战和潜在策略，从而提高 AAV 基因治疗的治疗潜力。
