Pursuing purine pathways to clinical trials for Parkinson's disease

背景：到目前为止，还没有发现一种治疗方法可以减缓帕金森病（PD）的潜在神经变性和由此导致的不可阻挡的临床进展。PD风险的流行病学和遗传学线索已经开始在寻找疾病修饰策略时提出新的分子靶点。在神经流行病学和帕金森病实验室模型的界面上，PI和他的同事们已经获得了两种普遍存在的嘌呤可能降低患帕金森病的风险的证据：咖啡因（腺苷受体拮抗剂）和尿酸盐（腺苷代谢的最终产物，人类的主要抗氧化剂）。此外，他们最近发现早期PD患者血液和脑脊液（CSF）中的尿酸盐是第一个已知的特发性PD临床进展的分子预测因子。虽然这种关联不涉及因果关系，但它为PD的病理生理学提供了有价值的新线索。在PI的指导下，这一发现已经导致了一项新的PD尿酸盐升高治疗的临床试验的发展，PI是帕金森研究组（PSG）经验丰富的临床研究者，也是基底神经节病理生理中腺苷受体的国际领先研究者和教育家。目标：在PI的基础科学和临床流行病学进展的基础上，该项目寻求建立一个转化研究和指导计划，追求嘌呤能途径成功的PD神经保护治疗。具体目标/设计：为了实现这一目标，PI和他的团队旨在：1)进一步将基线暴露于嘌呤（尿酸盐，其前体和咖啡因）与PD患者的临床进展率联系起来，并在PD小鼠模型中研究尿酸盐或其前体肌苷的保护作用。2)通过挖掘试验的生物学和临床数据库，并根据其结果开展III期疗效试验，最大限度地提高我们的尿酸盐前体肌苷（旨在评估其安全性和提高脑脊液尿酸盐的能力）的II期临床试验的产量。3)建立导师计划，将项目的临床研究机会与当地初级研究人员的职业发展结合起来，同时向全国神经内科住院医师和研究员教授转化神经科学方法。相关性：由NINDS K24奖提供的支持和保护时间将允许PI将其主要基于实验室的研究项目转变为致力于开发假定的神经保护剂的临床试验的完全集成的转化努力。尿酸盐是一个特别有希望的候选者，因为它具有前所未有的预测帕金森病风险和进展速度的能力，它的生物学合理性，以及它对药理学操作的适用性。该奖项还将有助于培训新一代临床神经科学家，使他们能够将分子见解转化为PD和其他神经退行性疾病患者的治疗进展。

DESCRIPTION (provided by applicant): Background: As yet no therapy has been found to slow the underlying neurodegeneration and the resultant inexorable clinical progression of Parkinson's disease (PD). Epidemiologic as well as genetic clues to the risk of PD have begun to suggest novel molecular targets in the search for disease-modifying strategies. Working at the interface of neuroepidemiology and laboratory models of PD, the PI and his colleagues have obtained convergent evidence that two ubiquitous purines might reduce the risk of developing PD: caffeine (an adenosine receptor antagonist) and urate (the end product of adenosine metabolism and a major antioxidant in humans). Moreover, they recently identified urate in the blood and cerebrospinal fluid (CSF) of early PD patients as the first known molecular predictor of clinical progression in idiopathic PD. Although the association does not address causality, it provides a valuable new clue to the pathophysiology of PD. This finding has already led to the development of a clinical trial of a novel urate-elevating treatment for PD under the direction of the PI, who is an experienced clinical investigator in the Parkinson Study Group (PSG) as well as a leading international investigator and educator on adenosine receptors in basal ganglia pathophysiology. Goal: Building on the PI's basic science and clinical epidemiology advances, the project seeks to establish a translational research and mentoring program that pursues purinergic pathways to successful neuroprotective therapy for PD. Specific Aims/Design: To achieve this goal the PI and his team aim to: 1) further correlate baseline exposures to purines (urate, its precursors, and caffeine) with rates of clinical progression in PD patients, and investigate a protective effect of urate or its precursor inosine in a mouse model of PD. 2) maximize the yield of our Phase II clinical trial of the urate precursor inosine (designed to assess its safety and ability to elevate CSF urate) by mining the trial's biological and clinical databases, and by developing a Phase III efficacy trial based on its results. 3) establish a mentorship program that integrates the project's clinical research opportunities with the career development of junior investigators locally, while teaching translational neuroscience approaches to neurology residents and fellows at the national level. Relevance: The support and protected time afforded by an NINDS K24 award will allow the PI to transition his primarily laboratory-based research program to a fully integrated translational endeavor dedicated to developing clinical trials of putative neuroprotective agents. Urate is a particularly promising candidate because of its unprecedented ability to predict both the risk of PD and its rate of progression, its biological plausibility, and its suitability to pharmacological manipulation. The award will also help ensure the training of a new generation of clinical neuroscientists capable of transforming molecular insights into therapeutic advances for patients with PD and other neurodegenerative diseases.