Multigene Marker of Progression in Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是一种无法治愈的进行性神经退行性疾病，在北美有100万人受到影响。在帕金森病的第二阶段和第三阶段临床试验中，迫切需要简单而可靠的血液测试来替代治疗反应，以确定主要的疾病修饰化合物的优先顺序。快速推进的基础研究正在创造一个正在进入临床试验的候选疾病修改疗法的不断扩大的管道。进展因限速瓶颈而受阻。在小型II期临床试验中，测试化合物的安全性和耐受性是直截了当的，但它们缺乏仅基于临床评估来检测疾病进展放缓的能力。因此，每一种化合物都必须经过大规模、昂贵和耗时的第三阶段临床试验，以决定其神经保护效果或失败。需要在第二阶段临床试验中跟踪帕金森病进展并可作为治疗效果替代的标记物，以确定第三阶段临床试验的先导化合物的优先顺序。最近，我们对来自帕金森病患者和匹配的健康和疾病对照组的105份血液样本中的22,000个基因进行了无偏向表达扫描。在这项横断面研究中，我们确定并初步验证了一个与帕金森病进展相关的32基因分子标记。它包括与疾病过程直接相关的细胞质量控制基因。在这里，我们将把基于微阵列的32基因进展特征转化为基于定量PCR的临床有用的血液检测，并在纵向研究中严格验证它。我们假设，从帕金森病患者血液中全基因组表达的变化可以得出疾病进展的简单测试。我们的具体目标是：1将微阵列衍生的候选者转化为基于定量PCR的简单的多基因PD进展测试；2在一项大型纵向研究中验证多基因进展标记，该研究在基线、一年和两年的随访中分析了150例病例和150名对照。这种用于跟踪疾病进展的简单和非侵入性测试将极大地加速PD患者新疗法的开发。帕金森病在北美影响着100万人，没有任何药物可以减缓疾病的进程。药物开发受到了速度限制瓶颈的限制。在第二阶段临床试验中，需要疾病进展的标志物作为疗效的替代指标，以确定第三阶段临床试验的先导化合物的优先顺序。这些进展标志物将极大地促进PD患者新疗法的发展。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disease without a cure that affects one million people in North America. Simple and robust blood tests that can serve as surrogates of treatment response are critically needed to prioritize lead disease-modifying compounds in phase II and III clinical trials in PD. Rapidly advancing basic research is creating an expanding pipeline of candidate disease-modifying therapeutics that are entering clinical trials. Progress has been curtailed by a rate- limiting bottleneck. In small phase II clinical trials, testing safety & tolerability of a compound is straightforward, however they lack power to detect slowing of disease progression based on clinical assessments alone. Therefore every compound has to go through large, costly and time-consuming phase III clinical trials to make decisions about its neuroprotective efficacy or failure. Markers that track the progression of PD in phase II clinical trials and that can serve as surrogates of therapeutic effect are needed to prioritize lead compounds for phase III clinical trials. Recently, we performed an unbiased expression scan of 22,000 genes in 105 blood specimens from patients with PD and matched healthy and disease controls. In this cross-sectional study we identified and initially validated a 32-gene molecular marker associated with progression in PD. It included genes involved in cellular quality control directly relevant to the disease process. Here we will transform the microarray-based 32- gene progression signature into a clinically useful blood test based on quantitative PCR and rigorously validate it in a longitudinal study. We hypothesize that a simple test of disease progression can be derived from genome-wide expression changes in blood of patients with PD. Our Specific Aims are: 1 To transform the microarray-derived candidates into a simple, multigene test of progression in PD based on quantitative PCR; 2 To validate the multigene progression marker in a large longitudinal study of 150 cases and 150 controls assayed at baseline, one-, and two-year follow-up visits. This simple and non-invasive test for tracking disease progression will greatly accelerate the development of novel therapeutics for PD patients. PD affects one million individuals in North America and no medications are available to slow the disease process. Drug development has been curtailed by a rate-limiting bottleneck. In phase II clinical trials markers of disease progression that can serve as surrogates of therapeutic effect, are needed to prioritize lead compounds for phase III clinical trials. These progression markers will greatly accelerate the development of novel therapeutics for PD patients.