DYSKINESIAS IN LENTI-GDNF TREATED PARKINSONIAN MONKEYS

胎儿黑质移植物可引起帕金森病患者的“失控”运动障碍（PD;Freed等人，2001年）。 这些运动障碍是严重的，使人衰弱的，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）这些运动障碍的潜在机制需要阐明。 我们最近已经证明，胶质细胞源性神经营养因子（GDNF）的慢病毒基因递送在PD的非人灵长类动物模型中有效地预防运动功能障碍并预防黑质纹状体变性（Kordower等人，2000年）。 在开始使用lenti-GDNF的临床试验之前，需要在帕金森病猴中评估其对运动障碍的作用。 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，以及来自其他人的数据（Kordower等人，1995，Lee et al 1999）不支持这一观点。 我们提出了一个替代假设，这些运动障碍的结果从局部“热点”的高多巴胺能功能与左旋多巴启动的大脑相互作用。 我们计划通过比较基因治疗对多巴诱导的运动障碍和多巴引发的作用诱导a）广泛或B）局部高多巴胺能功能来检验这一假设。 这项申请将有三个具体目标。 具体目标1将检验对非左旋多巴引发的MPTP处理的猴子的lenti-GDNF处理将预防或减少运动障碍的强度的假设，当它们随后用左旋多巴处理时。 具体目标2将检验以下假设：lenti-GDNF将减少先前用左旋多巴致敏的运动障碍MPTP治疗的猴子中的运动障碍特征。 具体目标3将检验“热点”多巴胺能功能亢进而非同质多巴胺能神经支配亢进将增强帕金森病猴的运动障碍特征以及GDNF的消除将逆转先前由该营养因子建立的功能和运动障碍效应的假设。 运动障碍的研究已成为PD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，使它们既安全又有效。本申请将确定是否有效的多巴胺能基因治疗影响运动障碍的最佳动物模型的PD。

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.