Regulatable promoters and gene therapy for Parkinson's disease: Is the only thing to fear, fear itself?
Regulatable promoters and gene therapy for Parkinson's disease: Is the only thing to fear, fear itself?
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DOI：
10.1016/j.expneurol.2007.08.001
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发表时间：
2008-01-01
影响因子：
5.3
通讯作者：
Olanow, C. Warren
中科院分区：
文献类型：
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作者：
Kordower, Jeffrey H.;Olanow, C. Warren
帕金森病的基因治疗已经成为临床现实，目前有三种不同的方法正在患者中进行测试。所有三项试验均采用具有2型血清型（AAV2）的腺相关病毒。迄今为止，在任何患者中均未报告与治疗性载体注射相关的严重不良事件。在某些情况下，根据啮齿动物和灵长类动物的详尽临床前试验预测了该安全性特征。还有一些人认为，可调控的启动子是必需的，这样转基因的表达就可以在出现不良副作用时停止。我们认为，鉴于目前的经验数据基础AAV2，缺乏已被证明是安全和有效的可调控的启动子，以及PD患者的迫切临床需求，强制使用可调控的载体不仅是不必要的，但在某些情况下，误导和潜在的危险。这篇评论将概述与使用可调控启动子进行PD基因治疗相关的问题，并表达我们的观点，即为什么强制使用此类启动子可能会导致不安全，非生产性的结果，并与科学合理的临床研究的进展背道而驰。(c)2007爱思唯尔公司All rights reserved.
Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research. (c) 2007 Elsevier Inc. All rights reserved.