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

AADC 基因转移对左旋多巴诱导的 MPTP 猴运动障碍的影响

• 批准号: 7613935
• 负责人: Robert Mark Richardson
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613935
• 关键词: Adverse effects; Amino Acids; Animal Model; Aromatic-L-Amino-Acid Decarboxylases; Basal Ganglia; Behavioral; Brain Part; Carboxy-Lyases; Clinical; Clinical Trials; Complication; Corpus striatum structure; Dependovirus; Diffuse; Dopamine; Dose-Limiting; Dyskinetic syndrome; Equilibrium; Gene Transfer; Human; Infusion procedures; Institution; Laboratories; Lesion; Levodopa; Metabolic; Methods; Modeling; Monkeys; Motor; Motor Pathways; Movement; Neurons; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Public Health; Quality of life; Recombinant adeno-associated virus (rAAV); Regulation; Research; Role; Techniques; Testing; Therapeutic; Toxic effect; Work; experience; follow-up; gene therapy; improved; nonhuman primate; pre-clinical; putamen; restoration

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.

描述（由申请人提供）：本提案的主要目的是检验以下假设：帕金森病（PD）中L-多巴诱导的运动障碍（LID）可以通过基因转移在纹状体中重新引入芳香族L-氨基酸脱羧酶（AADC）表达来改善。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，这是这种治疗最突出的运动并发症。LID反映了L-多巴转化效率的损失，这是PD患者L-多巴反应性进行性钝化的基础。将编码人AADC的重组腺相关病毒（AAV）（AAV-hAADC）输注到帕金森病猴的纹状体中导致神经元将外源施用的L-多巴转化为多巴胺（DA）的能力的实质性恢复。在我们机构的一项试验中，对接受AAV-hAADC纹状体输注的患者进行的初步临床随访表明，一些患者在基因转移后可能会经历LID降低。为了探索这种可能性，我们计划返回到临床前非人灵长类动物（NHP）模型，这两个具体的目标：以确定是否弥漫性表达AADC的过度损伤帕金森病猴壳核内产生LID减少，并将这些变化与左旋多巴相关的行为活动与左旋多巴诱导的代谢活动在基底神经节丘脑皮质回路内的区域变化。这些信息将显著增加我们对多巴胺在LID中的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，从而提高接受左旋多巴治疗的PD患者的生活质量。与公共卫生的相关性：大多数帕金森病患者最终会出现无法控制的运动，这是治疗药物的一种使人衰弱的副作用。这项研究在帕金森病的动物模型中使用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。