Effect of AADC gene transfer on L-dopa induced dyskinesia in MPTP monkeys

描述(申请人提供)：这项建议的广泛目标是检验这样一种假设，即通过基因转移，纹状体中重新引入芳香的L氨基酸脱羧酶(AADC)可以改善L-多巴诱导的帕金森病(PD)患者的运动障碍(LID)。L-多巴是帕金森病的主要治疗方法，尽管大多数患者最终会出现LID，这是这种治疗方法最突出的运动并发症。LID反映了L-多巴转换效率的丧失，这是PD患者L-多巴反应性进行性减退的基础。将编码人AADC的重组腺相关病毒(AAV-hAADC)注入帕金森病猴的斜带，可显著恢复神经元将外源性L-多巴转化为多巴胺(DA)的能力。在我们机构的一项试验中，对接受AAV-hAADC纹状体输注的患者的初步临床随访表明，一些患者在基因转移后可能会经历盖子减少。为了探索这种可能性，我们计划返回到临床前的非人灵长类动物模型，有这两个特定的目标：确定过度帕金森病猴壳核中AADC的弥漫性表达是否导致LID减少，以及将L-多巴相关的行为活动的这些变化与L-多巴诱导的基底节丘脑皮质回路中的代谢活动的区域变化相关联。这些信息将显著增加我们对多巴胺在LID中特定区域作用的理解，这将提高我们开发治疗方法的能力，从而提高接受L-多巴治疗的PD患者的生活质量。与公共健康相关：大多数帕金森氏症患者最终会出现无法控制的运动，这是治疗药物的一种令人衰弱的副作用。这项研究在帕金森氏病的动物模型中使用了神经外科基因治疗技术，以测试提高大脑特定部位的多巴胺水平是否可以缓解这些严重的副作用。

DESCRIPTION (provided by applicant): The broad objective of this proposal is to test the hypothesis that L-dopa-induced dyskinesias (LID) in Parkinson's disease (PD) can be ameliorated by the reintroduction of aromatic L-amino acid decarboxylase (AADC) expression in the striatum, via gene transfer. L-dopa is the mainstay therapy for PD, despite the fact that most patients eventually develop LID, the most prominent motor complication of this treatment. LID reflects a loss of L-dopa conversion efficiency that underlies the progressive blunting of L-dopa responsiveness in PD patients. Infusion of a recombinant adeno-associated virus (AAV) encoding human AADC (AAV-hAADC) into the straitum of Parkinsonian monkeys leads to substantial restoration of neuronal ability to convert exogenously administered L-dopa into dopamine (DA). Preliminary clinical follow-up of patients receiving striatal infusions of AAV-hAADC, in a trial at our institution, has suggested that some patients may experience reduced LID following gene transfer. To explore this possibility, we plan to return to the preclinical nonhuman primate (NHP) model, with these two specific aims: to determine whether diffuse expression of AADC within the putamen of over-lesioned parkinsonian monkeys produces a reduction in LID, and to correlate these changes in L-dopa associated behavioral activity with regional changes in L-dopa induced metabolic activity within the basal ganglia thalamocortical circuitry. This information will significantly increase our understanding of the region-specific role of dopamine in LID, which will improve our ability to develop treatments that enhance the quality of life for PD patients receiving L-dopa therapy. RELEVANCE TO PUBLIC HEALTH: Most patients with Parkinson's disease eventually develop uncontrollable movements that are a debilitating side-effect of therapeutic medication. This research uses a neurosurgical gene therapy technique in an animal model of Parkinson's disease, to test whether increasing the level of dopamine in a specific part of the brain can relieve, these severe side-effects.