Department of Biochemical Engineering, University College London, London, WC1E 6BT, UK.
Gene Ther. 2023 Apr;30(3-4):323-335. doi: 10.1038/s41434-022-00363-0. Epub 2022 Sep 12.
Gene therapy has seen a transformation from a proof-of-concept approach to a clinical reality over the past several decades, with adeno-associated virus (AAV)-mediated gene therapy emerging as the leading platform for in vivo gene transfer. A systematic review of AAV-based gene therapies in clinical development was conducted herein to determine why only a handful of AAV-based gene therapy products have achieved market approval. The indication to be treated, route of administration and vector design were investigated as critical factors and assessed for their impact on clinical safety and efficacy. A shift in recent years towards high-dose systemic administration for the treatment of metabolic, neurological and haematological diseases was identified, with intravenous administration demonstrating the highest efficacy and safety risks in clinical trials. Recent years have seen a decline in favour of traditional AAV serotypes and promoters, accompanied by an increase in favour and higher clinical success rate for novel capsids and tissue-specific promoters. Furthermore, a meta-analysis was performed to identify factors that may inhibit the translation of therapeutic efficacy from preclinical large animal studies to first-in-human clinical trials and a detrimental effect on clinical efficacy was associated with alterations to administration routes.
在过去的几十年中，基因治疗已经从概念验证方法转变为临床现实，腺相关病毒 (AAV) 介导的基因治疗已成为体内基因转移的主要平台。本文对临床开发中的基于 AAV 的基因治疗进行了系统评价，以确定为什么只有少数基于 AAV 的基因治疗产品获得了市场批准。研究了治疗适应症、给药途径和载体设计作为关键因素，并评估了它们对临床安全性和疗效的影响。近年来，人们越来越倾向于采用高剂量全身给药来治疗代谢、神经和血液疾病，静脉给药在临床试验中显示出最高的疗效和安全性风险。近年来，传统的 AAV 血清型和启动子的应用有所减少，而新型衣壳和组织特异性启动子的应用则有所增加，且具有更高的临床成功率。此外，还进行了荟萃分析，以确定可能抑制从临床前大型动物研究到首次人体临床试验的治疗疗效转化的因素，并且给药途径的改变与临床疗效的不利影响相关。
