Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Signal Transduct Target Ther. 2024 Apr 3;9(1):78. doi: 10.1038/s41392-024-01780-w.
Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.
腺相关病毒（AAV）因其致病性低且能够在不同组织中建立长期基因表达而成为临床基因治疗的重要载体。为了提高特异性，研究人员对重组腺相关病毒（rAAV）进行了工程改造，并将其开发为治疗各种疾病的工具。然而，随着 rAAV 在治疗中的应用越来越广泛，对现有制造方法的需求增加带来了挑战。目前已有七种基于 rAAV 的基因治疗产品获得了监管部门的批准，但人们仍对在人类中使用高剂量病毒疗法的安全性表示担忧，包括免疫反应和遗传毒性、肝毒性、血栓性微血管病和神经毒性等不良反应。在这篇综述中，我们重点探讨了 AAV 的生物学特性，包括当前的载体工程策略和制造技术。我们讨论了正在进行的眼部、神经、代谢、血液、神经肌肉和心血管疾病以及癌症的临床试验中如何使用 rAAV。我们概述了 rAAV 引发的免疫反应，解决了相关的副作用问题，并讨论了减轻这些反应的策略。我们希望讨论该领域的最新进展和当前挑战，能为研究人员和临床医生提供有益的指导，帮助他们应对 rAAV 基因治疗领域不断变化的格局。
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