Multigene Marker of Progression in Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）是一种无法治愈的进行性神经退行性疾病，在北美影响着100万人。在帕金森病的II期和III期临床试验中，迫切需要简单而可靠的血液检测来替代治疗反应。快速推进的基础研究正在创造一个不断扩大的候选疾病修饰疗法管道，这些疗法正在进入临床试验。进度受到速率限制瓶颈的限制。在小型II期临床试验中，检测化合物的安全性和耐受性很简单，但它们缺乏仅基于临床评估来检测疾病进展减缓的能力。因此，每种化合物都必须经过大规模、昂贵和耗时的III期临床试验，以确定其神经保护功效或失败。需要在II期临床试验中跟踪PD进展的标记物，并可以作为治疗效果的替代品，以优先考虑III期临床试验的先导化合物。最近，我们对来自PD患者以及匹配的健康和疾病对照者的105个血液样本进行了22,000个基因的无偏表达扫描。在这项横断面研究中，我们确定并初步验证了与PD进展相关的32个基因分子标记。它包括参与与疾病过程直接相关的细胞质量控制的基因。在这里，我们将把基于微阵列的32个基因进展标记转化为基于定量PCR的临床有用的血液检测，并在纵向研究中严格验证它。我们假设可以从PD患者血液中全基因组表达的变化中获得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基因转化为基于定量PCR的PD进展的简单多基因测试；2在一项大型纵向研究中验证多基因进展标志物，该研究包括150例病例和150例对照，在基线、1年和2年随访期间进行分析。这种简单且无创的追踪疾病进展的测试将极大地加速PD患者新疗法的发展。在北美，PD影响了100万人，没有药物可以减缓疾病的进程。药物开发受到速度限制瓶颈的限制。在II期临床试验中，需要疾病进展标志物作为治疗效果的替代指标来优先考虑III期临床试验的先导化合物。这些进展标记物将极大地加速PD患者新疗法的开发。

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.