rAAV Human Trial Experience
rAAV Human Trial Experience
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DOI：
10.1007/978-1-61779-370-7_18
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Aubourg, Patrick
中科院分区：
文献类型：
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作者：
High, Katherine A.;Aubourg, Patrick
自 20 世纪 90 年代中期以来，重组 AAV 载体已用于临床试验，已有 300 多名受试者参加了研究。尽管目前还没有获得许可的 AAV 产品，但已经有几个明显的临床疗效实例，并且重组 AAV 载体在局部和全身给药后都具有很强的安全性记录。本章回顾了已显示疗效的两类研究，包括针对莱伯先天性黑蒙（一种遗传性视网膜退行性疾病）的研究，其中视网膜下注射 AAV 在改善视觉/视网膜功能的多项指标方面显示出功效；以及帕金森病，在基因转移到中枢神经系统后，临床和影像学研究也显示出改善。本章还详细回顾了血友病基因治疗的研究结果，其中取得了短期疗效，但捐赠基因的表达未能持续，可能是由于对载体的免疫反应。讨论了与 AAV 介导的基因转移相关的安全问题，包括对 AAV 基因治疗试验中发生的单例死亡（可能与 AAV 载体无关）的详细审查，以及与整合和插入突变相关的问题、种系传播的风险以及与载体或转基因产品的免疫反应相关的风险。最后，详细描述了使用实时定量 PCR 确定体液中载体 DNA 的存在，以及分离、冷冻保存和测试外周血单核细胞对衣壳的干扰素-γ (IFN-γ) 反应的方案。
Recombinant AAV vectors have been used in clinical trials since the mid-1990s, with over 300 subjects enrolled in studies. Although there are not yet licensed AAV products, there are several clear examples of clinical efficacy, and recombinant AAV vectors have a strong safety record after administration both locally and systemically. This chapter provides a review of two types of studies that have shown efficacy, including studies for Leber's congenital amaurosis, a hereditary retinal degenerative disorder in which subretinal administration of AAV has shown efficacy in terms of improvement in multiple measures of visual/retinal function; and of Parkinson's disease which has also shown improvement in clinical and imaging studies after gene transfer to the CNS. The chapter also provides a detailed review of the results of studies of gene therapy for hemophilia, in which short-term efficacy was achieved, but expression of the donated gene failed to persist, likely due to an immune response to the vector. Safety issues relating to AAV-mediated gene transfer are discussed, including a detailed review of the single death to have occurred in an AAV gene therapy trial (likely unrelated to the AAV vector), and of issues related to integration and insertional mutagenesis, risk of germline transmission, and risks related to immune responses to either vector or transgene product. Finally, protocols for determining the presence of vector DNA in body fluids using real-time quantitative PCR, and for isolating, cryopreserving, and testing peripheral blood mononuclear cells for interferon-gamma (IFN-gamma) responses to capsid are described in detail.