Biomarkers for early intervention in Parkinson disease

描述(申请人提供)：目前尚无治愈方法，但预计2030年帕金森氏症患者的数量将增加近一倍，达到930万人。有两个障碍阻碍了疾病修正疗法的进展。目前的临床试验因诊断较晚而受阻，依赖于潜在神经病理学进展很快时发生的运动受损。此外，在第二阶段临床试验中，测试化合物的安全性和耐受性是直截了当的，但目前基于症状的措施无法检测到药物对潜在疾病过程的影响。在这里，我们提出了克服这些障碍的具体和一般战略。超过9万个非蛋白质编码、调控的RNA可能解释了人类大脑在健康和疾病中的复杂性。数以千计的这些先前隐藏的RNA富含多巴胺能神经元，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，直接反映了改变的生理，而不翻译成蛋白质。这为生物标记物的开发提供了一个潜在的突破性机会。首先，我们将利用大规模平行测序和无限转录组重建，在激光从100个人脑中捕获的多巴胺神经元中系统地描绘与早期帕金森氏症神经病理相关的所有非编码RNA。然后，我们将把与最早的神经病理过程有关的调控RNA转化为数字生物标记物，分别在242名和167名受试者的血液和脑脊液中检测到。为了建立一条普遍有用的生物标志物开发快车道，我们建议哈佛与NINDS建立合作伙伴关系。它将利用无与伦比的基础设施，并提供一个纵向帕金森氏生物库--一个催化的、开放的平台，用于启动PD生物标记物的发现和验证。辅助脑脊液收集将在哈佛神经发现中心生物标记物研究中进行，这是一项纵向的病例对照研究，已经跟踪了1886名帕金森氏症患者和对照患者的临床表型和相关的生物样本。这项研究将发现和翻译可行的生物标记物，用于帕金森氏病的早期检测过程，并有助于为生物标记物的开发开辟一条普遍有用的快车道。 与公共健康相关：目前还没有治愈的方法，但预计2030年帕金森氏症患者的数量将增加近一倍，达到930万人，对公共健康构成越来越大的威胁，仅在美国每年的成本估计就高达108亿美元。我们提出了一个具体的和一般的战略，以克服两个阻碍疾病修正疗法开发进展的关键障碍。

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.