Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, United States; Department of Neurology, University of Massachusetts Chan Medical School, United States; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, United States.
Graduate Program in Translational Science, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, United States; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, United States.
Neurotherapeutics. 2024 Jul;21(4):e00435. doi: 10.1016/j.neurot.2024.e00435. Epub 2024 Aug 23.
Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.
腺相关病毒 (AAV) 介导的基因治疗是一种领先的基因传递平台，具有改变神经疾病治疗格局的潜力。虽然与其他病毒载体相比，AAV 被认为是非免疫原性的，但在临床中已经观察到了不良反应免疫反应，引起了人们的关注。由于中枢神经系统 (CNS) 具有高度调节的免疫系统，具有一定程度的耐受性，因此被认为是 AAV 基因治疗的独特靶标。AAV 载体已显示出治疗几种 CNS 疾病的有希望的结果，包括脊髓性肌萎缩症、巨大轴索神经病、肌萎缩侧索硬化症、泰萨克斯病、帕金森病等，证明了其安全性和有效性。美国食品和药物管理局 (FDA) 批准的 Zolgensma 和欧洲药品管理局 (EMA) 批准的 Upstaza 分别用于治疗脊髓性肌萎缩症 (SMA) 和芳香族 l-氨基酸脱羧酶缺乏症 (AADC)，代表了这一成功，同时强调了对 AAV 的免疫反应存在显著差异，特别是在治疗给药途径方面。像 Upstaza 这样直接注射到免疫特化脑内的 AAV 疗法具有轻度免疫反应谱和较少的不良事件特征，而像 Zolgensma 这样全身注射的疗法则表现出更强的免疫刺激和脱靶毒性。尽管存在这些对比鲜明的平行现象，但这些疗法和临床中的其他疗法已经为患者带来了临床益处，需要进一步探索针对 CNS 的 AAV 临床试验中的免疫反应。因此，在这篇综述中，我们讨论了 AAV 给药途径的不同对中枢神经系统靶向试验中观察到的局部和外周免疫反应的影响。
