TH and GTPCHI gene therapy for Parkinson's disease

描述（由申请人提供）：本提案汇集了三个经验丰富的小组，提出了在帕金森病（PD）的啮齿动物（隆德）和非人灵长类动物（Rush）模型中使用腺相关病毒（Gainesville）的综合系列实验。一个共识是出现位点特异性rAAV介导的纹状体左旋多巴交付可能是一个有用的策略，用于治疗PD。然而，在需要进行关键的有效性和安全性研究之前，甚至不能开始考虑使用这种方法的临床试验。为此，本申请将探讨三个研究主题。首先，我们将在载体优化设计的猴子中进行研究。我们将在非人灵长类动物中确定最佳的AAV血清型，并建立TH与GTPCH 1的最佳比例。然而，我们相信，由于GTPCH 1的动力学，更高的比率将更有效，因此我们将能够递送更多的TH，并最终递送更多的LDOPA。这些研究还将提供灵长类动物的关键“放大”数据，这些数据将与未来的临床试验相关。第二个研究主题是功效。TH/GTPCH 1基因递送方法已经被证明在逆转PD啮齿动物模型中药物诱导的和自发的运动缺陷中是有效的。本提案将在MPTP治疗的猴中确定疗效，这是PD可用的最佳动物模型。第三个目标是安全。关于功能安全，我们主要担心的是运动障碍。我们已经证明，rAAV-Ldopa逆转已经在6-OHDA损伤的大鼠中表现出运动障碍，并且有新的数据证明rAAV-LDOPA防止运动障碍的出现。在这个新的应用中，我们将评估5-羟色胺在大鼠运动障碍表达中的作用。此外，将评价TH/GTPCH 1的“热点”与“广泛”递送对功效和运动障碍的影响。运动障碍的猴模型被认为是运动障碍研究的最佳可用模型。在本研究中，我们将测试基因递送左旋多巴既可以逆转已经表现出的Idopa运动障碍又可以延迟新的运动障碍的出现的假设。这些研究将确定LDOPA基因递送的安全性和有效性，并确定这种方法是否适用于临床试验。

DESCRIPTION (provided by applicant): This proposal brings together three experienced groups proposing an integrated series of experiments using adeno-associated virus (Gainesville) in rodent (Lund) and nonhuman primate (Rush) models of Parkinson's disease (PD). A concensus is emerging that site-specific rAAV-mediated striatal L-dopa delivery might be a useful strategy for treating PD. However, clinical trials using this approach cannot even begin to be considered before critical efficacy and safety studies need to be performed. Towards this end, three research themes will be explored in this application. First we will perform studies in monkeys designed at vector optimization. We will determine the optimal AAV serotype in nonhuman primates and establish the optimal ratio of TH to GTPCH1.Currently, a 1:1 ratio is utilized. However, we believe that a higher ratio will be more effective due to the kinestics of GTPCH1 and thus we will be able to deliver more TH, and ultimately more LDOPA. These studies will also provide critical "scaling-up" data in primates that will be relevant for futures clinical trials. The second research theme is efficacy. The TH/GTPCH1 gene delivery approach has already been shown to be effective in reversing drug-induced and spontaneous motor deficits in rodent models of PD. The present proposal will establish efficacy in MPTP treated monkeys, the best animal model available for PD. The third aim is safety. With regards to functional safety, our main concern is dyskinesias. We have already demonstrated that rAAV-Ldopa reverses already manifest dyskinesias in 6-OHDA lesioned rats and have new data demonstrating that rAAV-LDOPA prevents the emergence of dyskinesias. IN this new application, we will evaluate the role of serotonin in the expression of dyskinesias in rats. Further, the effect of "hot spot" versus "widespread" delivery of TH/GTPCH1 upon efficacy and dyskinesias will be evaluated. The monkey model of dyskinesias is recognized as the best available for the study of dyskinesias. In the present study we will test the hypothesis that gene delivered levodopa can both reverse already manifest Idopa dyskinesias and delay the emergence of new dyskinesias. These studies will determine the safety and efficacy of gene delivery of LDOPA and determine whether this approach is appropriate for clinical trials.