Department of Paediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
Nat Rev Drug Discov. 2023 Oct;22(10):789-806. doi: 10.1038/s41573-023-00766-7. Epub 2023 Sep 1.
Recent advancements in gene supplementation therapy are expanding the options for the treatment of neurological disorders. Among the available delivery vehicles, adeno-associated virus (AAV) is often the favoured vector. However, the results have been variable, with some trials dramatically altering the course of disease whereas others have shown negligible efficacy or even unforeseen toxicity. Unlike traditional drug development with small molecules, therapeutic profiles of AAV gene therapies are dependent on both the AAV capsid and the therapeutic transgene. In this rapidly evolving field, numerous clinical trials of gene supplementation for neurological disorders are ongoing. Knowledge is growing about factors that impact the translation of preclinical studies to humans, including the administration route, timing of treatment, immune responses and limitations of available model systems. The field is also developing potential solutions to mitigate adverse effects, including AAV capsid engineering and designs to regulate transgene expression. At the same time, preclinical research is addressing new frontiers of gene supplementation for neurological disorders, with a focus on mitochondrial and neurodevelopmental disorders. In this Review, we describe the current state of AAV-mediated neurological gene supplementation therapy, including critical factors for optimizing the safety and efficacy of treatments, as well as unmet needs in this field.
近年来，基因补充治疗的进展为治疗神经紊乱提供了更多的选择。在现有的各种传递载体中，腺相关病毒（AAV）通常是首选的载体。然而，结果却各不相同，一些试验显著改变了疾病的进程，而另一些试验则显示出微不足道的疗效，甚至是意想不到的毒性。与小分子的传统药物开发不同，AAV 基因治疗的治疗谱取决于 AAV 衣壳和治疗性转基因。在这个快速发展的领域，针对神经紊乱的基因补充的许多临床试验正在进行中。人们越来越了解影响临床前研究向人体转化的因素，包括给药途径、治疗时机、免疫反应和现有模型系统的局限性。该领域还在开发潜在的解决方案来减轻不良反应，包括 AAV 衣壳工程和调节转基因表达的设计。与此同时，临床前研究正在为神经紊乱的基因补充开辟新的前沿，重点是线粒体和神经发育紊乱。在这篇综述中，我们描述了 AAV 介导的神经基因补充治疗的现状，包括优化治疗安全性和疗效的关键因素，以及该领域的未满足需求。
