Biomarkers for early intervention in Parkinson disease

描述（由申请人提供）：目前还没有治愈方法，但帕金森病患者的数量预计将在2030年增加近一倍，达到930万。两个障碍阻碍了疾病修饰疗法的进展。目前的临床试验受到晚期诊断的阻碍，依赖于在潜在神经病理已经严重恶化时发生的运动受损。此外，在II期临床试验中，检测化合物的安全性和耐受性很简单，但目前基于症状的措施无法检测药物对潜在疾病过程的影响。在此，我们提出一项克服这些障碍的具体和总体战略。超过90,000种非蛋白质编码、调控rna可能解释了人类大脑在健康和疾病中的复杂性。这些先前隐藏的rna在多巴胺能神经元中大量存在，并调节帕金森病的基因表达和参与疾病发病的生物能量学过程。调控rna整合了环境、表观遗传和遗传变异，直接反映生理变化，而不翻译成蛋白质。这为生物标志物的开发提供了一个潜在的突破性机会。首先，我们将系统地描述与多巴胺神经元早期帕金森神经病理相关的所有非编码rna，这些非编码rna是从100个人脑中激光捕获的，使用大规模平行测序和无限转录组重建。然后，我们将把与早期神经病理过程相关的调控rna转化为分别在242名和167名受试者的血液和脑脊液中检测到的数字生物标志物。为了建立一个普遍有用的生物标志物开发的快速通道，我们建议哈佛大学与ninds合作。它将利用无与伦比的基础设施，提供一个纵向的帕金森生物库——一个催化的、开放的平台，用于启动帕金森生物标志物的发现和验证。辅助脑脊液收集将在哈佛神经发现中心生物标志物研究中进行，这是一项纵向病例对照研究，已经追踪了bb101,886名帕金森病患者和对照组的临床表型和相关生物标本。这项研究将发现和翻译可行的生物标志物，用于帕金森病过程的早期检测，并为生物标志物的开发提供一条普遍有用的快速通道。

DESCRIPTION (provided by applicant): No cures exist, but the number of Parkinson's patients is expected to nearly double to 9.3 million in 2030. Two roadblocks impede progress on disease-modifying therapeutics. Current clinical trials are handicapped by late diagnosis, relying on impaired movements that occur when underlying neuropathology has far advanced. Moreover, in phase II clinical trials, testing safety and tolerability of a compound is straightforward, but drug effects on the underlying disease processes cannot be detected by current symptom-based measures. Here we propose a specific and a general strategy to overcome these roadblocks. More than 90,000 non-protein coding, regulatory RNAs may account for the complexity of the human brain in health and disease. Thousands of these previously hidden RNAs abound in dopaminergic neurons and regulate Parkinson's gene expression and bioenergetics processes involved in the disease onset. Regulatory RNAs integrate environmental, epigenetic, and genetic variation and directly reflect altered physiology without translation into protein. This offers a potentially ground breaking opportunity for biomarker development. Initially, we will systematically delineate all non-coding RNAs associated with incipient Parkinson's neuropathology in dopamine neurons laser-captured from 100 human brains using massively parallel sequencing and unlimited transcriptome reconstruction. Then, we will translate regulatory RNAs linked to the earliest neuropathological processes into digital biomarkers detectable in bloodstream and cerebrospinal fluid of 242 and 167 subjects, respectively. To build a generally useful express lane for biomarker development we propose a Harvard-NINDS partnership. It will leverage an unparalleled infrastructure and deliver a longitudinal Parkinson's biobank -- a catalytic, open platform for jump-starting the discovery and validation of PD biomarkers. Ancillary cerebrospinal fluid collection will be performed in the Harvard NeuroDiscovery Center Biomarker Study, a longitudinal, case-control study that already tracks clinical phenotypes and linked biospecimens of >1,886 individuals with Parkinson's disease and controls. This study will discover and translate viable biomarkers for the early detection of Parkinson's disease processes and contribute to a generally useful express lane for biomarkers development. PUBLIC HEALTH RELEVANCE: No cures exist, but the number of Parkinson's patients is expected to nearly double to 9.3 million in 2030 posing an increasing threat to public health with annual costs estimated at $10.8 billion in the US alone. We propose a specific and a general strategy to overcome two critical roadblocks that impede progress on developing disease-modifying therapeutics.