DYSKINESIAS IN LENTI-GDNF TREATED PARKINSONIAN MONKEYS

胎儿神经移植可引起帕金森病患者“失控”的运动障碍（PD;Freed etal ., 2001）。这些运动障碍是严重的，使人衰弱，并且强烈表明：1)计划用于临床试验的新型多巴胺能手术治疗策略需要在临床前测试其对运动障碍的影响；2)这些运动障碍的机制需要阐明。我们最近证明，慢病毒基因传递神经胶质细胞源性神经营养因子（GDNF）能有效预防PD非人灵长类模型的运动功能障碍和黑质纹状体变性（Kordower等，2000）。在进行lentit - gdnf的临床试验之前，需要在帕金森猴中评估其对运动障碍的影响。Freed、Fahn和同事（2001）假设移植物介导的运动障碍是由移植物过度生长引起的。然而，他们自己的PET和死后数据，以及其他人的数据（Kordower et al., 1995, Lee et al. 1999）都不支持这一观点。我们提出了另一种假设，即这些运动障碍是由高多巴胺能功能的局部“热点”与左旋多巴启动的大脑相互作用引起的。我们计划通过比较在多巴诱导的运动障碍中诱导a)广泛或b)局部高多巴胺能功能的基因疗法和多巴启动的作用来验证这一假设。此应用程序将有三个具体目标。特异性目标1将检验一种假设，即对未左旋多巴启动的mptp治疗的猴子进行慢体- gdnf治疗，可以预防或减轻它们随后接受左旋多巴治疗时运动障碍的强度。特异性目标2将测试假设，即lentit - gdnf将减少先前用左旋多巴启动的mptp治疗的运动障碍猴子的运动障碍特征。特异性目标3将验证“热点”高多巴胺能功能，而不是均匀的高多巴胺能神经支配，将增强帕金森猴子的运动障碍特征，并且消除GDNF将逆转先前由这种营养因子建立的功能和运动障碍效应。运动障碍的研究已成为帕金森病研究的一个引人注目的领域。令人兴奋的治疗策略，如基因治疗，需要评估其对运动障碍的影响，以确保它们既安全又有效。这项应用将确定有效的多巴胺能基因疗法是否影响帕金森病最佳动物模型中的运动障碍。

Fetal nigral grafts can cause "runaway" dyskinesias in patients with Parkinson's disease (PD;Freed et al., 2001). These dyskinesias are severe, debilitating and strongly indicate that 1) novel dopaminergic surgical therapeutic strategy planned for clinical trials need to be tested preclinically for their effects upon dyskinesias and 2) the mechanisms underlying these dyskinesias need to be elucidated. We have recently demonstrated that lentiviral gene delivery of glial cell-derived neurotrophic factor (GDNF) potently prevents motor dysfunction and prevents nigrostriatal degeneration in nonhuman primate models of PD (Kordower et al., 2000). Prior to initiating clinical trials with lenti-GDNF, it effects upon dyskinesias need to be evaluated in parkinsonian monkeys. Freed, Fahn and coworkers (2001) have hypothesized that grafted-mediated dyskinesias result from graft overgrowth. However, their own PET and post-mortem data, as well as the data from others (Kordower et al., 1995, Lee et al 1999), do not support this view. We propose an alternative hypothesis that these dyskinesias result from local "hot spots" of hyperdopaminergic function interacting with the levodopa primed brain. We plan to test this hypothesis by comparing gene therapies that induce either a) widespread or b) local hyperdopaminergic function upon dopa-induced dyskinesias and the role of dopa priming. This application will have three Specific Aims. Specific Aim 1 will test the hypothesis that lenti-GDNF treatment to non-levodopa primed MPTP-treated monkeys will prevent, or diminish the intensity of dyskinesias when they are later treated with levodopa. Specific Aim 2 will test the hypothesis that lenti-GDNF will diminish the dyskinesia profile in dyskinesic MPTP-treated monkeys previously primed with levodopa. Specific Aim 3 will test the hypothesis that "hot- spot" hyperdopaminergic function, but not homogenous hyperdopaminergic innervation, will enhance the dyskinesia profile of parkinsonian monkeys and that elimination of GDNF will reverse the functional and dyskinesic effects established previously by this trophic factor. The study of dyskinesias has become a compelling area of PD research. Exciting therapeutic strategies such as gene therapy need to be evaluated for their effects on dyskinesias so that they are both safe and effective. This application will determine whether potent dopaminergic gene therapies influence dyskinesias in the best animal model of PD.