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

描述（由申请人提供）：本提案的主要目的是验证左旋多巴诱导的帕金森病（PD）运动障碍（LID）可以通过基因转移在纹状体中重新引入芳香l -氨基酸脱羧酶（AADC）表达来改善的假设。左旋多巴是PD的主要治疗方法，尽管大多数患者最终会发展为LID，这是该治疗最突出的运动并发症。LID反映了左旋多巴转换效率的丧失，这是PD患者左旋多巴反应性进行性钝化的基础。将编码人类AADC （AAV- haadc）的重组腺相关病毒（AAV- haadc）输注到帕金森猴的网膜中，可显著恢复神经元将外源性左旋多巴转化为多巴胺（DA）的能力。在我们机构的一项试验中，对接受纹状体注射AAV-hAADC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出现LID降低。为了探索这种可能性，我们计划回到临床前非人灵长类动物（NHP）模型，有两个具体目的：确定过度受损的帕金森猴壳核内AADC的弥漫性表达是否会导致LID的减少，以及将左旋多巴相关行为活动的变化与左旋多巴诱导的基底神经节丘脑皮质回路内代谢活动的区域变化联系起来。这一信息将大大增加我们对多巴胺在LID中区域特异性作用的理解，这将提高我们开发治疗方法的能力，提高接受左旋多巴治疗的PD患者的生活质量。与公共卫生相关：大多数帕金森病患者最终会出现无法控制的运动，这是治疗药物的副作用。这项研究在帕金森病的动物模型中使用了一种神经外科基因治疗技术，以测试增加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.