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（Lund）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。一种共识正在形成，即位点特异性raav介导的纹状体左旋多巴递送可能是治疗PD的有效策略。然而，在需要进行关键的疗效和安全性研究之前，甚至不能开始考虑使用这种方法的临床试验。为此，本应用程序将探讨三个研究主题。首先，我们将在设计矢量优化的猴子身上进行研究。我们将确定非人灵长类动物的最佳AAV血清型，并确定TH与GTPCH1的最佳比例。目前，使用1:1的比例。然而，我们认为，由于GTPCH1的动力学，更高的比例将更有效，因此我们将能够提供更多的TH，最终更多的LDOPA。这些研究还将为灵长类动物提供关键的“放大”数据，这将与未来的临床试验有关。第二个研究主题是功效。TH/GTPCH1基因递送方法已被证明在逆转药物诱导和自发性运动缺陷方面有效。本研究将在MPTP治疗的猴子身上建立疗效，这是目前治疗帕金森病的最佳动物模型。第三个目标是安全。关于功能安全，我们主要关注的是运动障碍。我们已经证明rAAV-Ldopa逆转了6-OHDA损伤大鼠已经出现的运动障碍，并且有新的数据表明rAAV-Ldopa可以防止运动障碍的出现。在这个新的应用中，我们将评估血清素在大鼠运动障碍表达中的作用。此外，将评估“热点”与“广泛”递送TH/GTPCH1对疗效和运动障碍的影响。运动障碍的猴子模型被认为是研究运动障碍的最佳模型。在目前的研究中，我们将验证基因传递的左旋多巴既可以逆转已经出现的多巴运动障碍，又可以延缓新的运动障碍的出现。这些研究将确定LDOPA基因传递的安全性和有效性，并确定该方法是否适合临床试验。

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.