Chandler Randy J, Sands Mark S, Venditti Charles P
1 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health , Department of Health and Human Services, Bethesda, Maryland.
2 Department of Internal Medicine, Washington University School of Medicine , St. Louis, Missouri.
Hum Gene Ther. 2017 Apr;28(4):314-322. doi: 10.1089/hum.2017.009.
Currently, clinical gene therapy is experiencing a renaissance, with new products for clinical use approved in Europe and clinical trials for multiple diseases reporting positive results, especially those using recombinant adeno-associated viral (rAAV) vectors. Amid this new success, it is prudent to recall that the field of gene therapy experienced tragic setbacks in 1999 and 2002 because of the serious adverse events related to retroviral and adenoviral gene delivery in two clinical trials that resulted in the death of two patients. In both cases, the toxicity observed in humans had been documented to occur in animal models. However, these toxicities were either undetected or underappreciated before they arose in humans. rAAVs have been tested extensively in animals and animal models of disease, largely without adverse events, except for transient elevation in liver enzymes in some patients. However, a small but growing number of murine studies have documented that adeno-associated viral gene delivery can result in insertional mutagenesis. Herein, the aggregate data are reviewed from multiple murine studies where genotoxicity associated with rAAV treatment has been observed. The data emphasize the need for a proactive position to evaluate the potential risks and possible solutions associated with AAV-mediated gene therapy.
目前，临床基因治疗正在复兴，欧洲已批准了用于临床的新产品，针对多种疾病的临床试验也报告了积极结果，尤其是那些使用重组腺相关病毒（rAAV）载体的试验。在这一新的成功之际，审慎回顾一下基因治疗领域在1999年和2002年经历的悲剧性挫折是很有必要的，当时两项临床试验中逆转录病毒和腺病毒基因递送引发了严重不良事件，导致两名患者死亡。在这两起案例中，在动物模型中已记录到人类中观察到的毒性。然而，这些毒性在出现在人类身上之前要么未被发现，要么未得到充分重视。rAAV已在动物和疾病动物模型中进行了广泛测试，除了一些患者的肝酶短暂升高外，基本上没有不良事件。然而，越来越多的小鼠研究记录表明，腺相关病毒基因递送可导致插入诱变。本文回顾了多项观察到与rAAV治疗相关的基因毒性的小鼠研究的汇总数据。这些数据强调需要采取积极立场来评估与AAV介导的基因治疗相关的潜在风险和可能的解决方案。
