DYSKINESIAS IN LENTI-GDNF TREATED PARKINSONIAN MONKEYS

胎儿黑质移植物可导致帕金森氏病患者的“失控”运动障碍(PD；Freed等人，2001)。这些运动障碍是严重的、令人衰弱的，并强烈表明：1)计划用于临床试验的新的多巴胺能外科治疗策略需要在临床前测试其对运动障碍的影响；2)这些运动障碍的潜在机制需要阐明。我们最近在非人类灵长类动物模型中证明了慢病毒基因传递胶质细胞衍生神经营养因子(GDNF)有效地防止了运动功能障碍和黑质纹状体变性(Kordower等人，2000)。在开始Lenti-GDNF的临床试验之前，需要评估它对帕金森病猴子运动障碍的影响。Freed、Fahn和他的同事(2001)假设移植物介导的运动障碍是移植物过度生长所致。然而，他们自己的PET和尸检数据以及来自其他人的数据(Kordower等人，1995年，Lee等人1999年)并不支持这一观点。我们提出了另一种假说，认为这些运动障碍是由于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所致。我们计划通过比较在多巴诱导的运动障碍中诱导a)广泛的或b)局部的多巴胺能功能的基因疗法和多巴启动的作用来检验这一假设。这个应用程序将有三个具体目标。具体目标1将检验这样的假设，即Lenti-GDNF治疗非左旋多巴诱导的MPTP治疗的猴子将防止或减少稍后用左旋多巴治疗时的运动障碍的强度。特定目标2将测试Lenti-GDNF将减少运动障碍MPTP治疗猴子运动障碍的假设，这些猴子以前用过左旋多巴。具体目标3将测试这样一种假设，即“热点”的高多巴胺能功能，而不是同质的高多巴胺能神经支配，将增强帕金森病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。运动障碍的研究已经成为帕金森病研究的一个引人注目的领域。需要评估基因疗法等令人兴奋的治疗策略对运动障碍的影响，以便它们既安全又有效。这项应用将确定有效的多巴胺能基因疗法是否会影响最佳帕金森病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.