Evaluation of glucocerebrosidase pathway biomarkers in Parkinson Disease

帕金森病葡萄糖脑苷脂酶途径生物标志物的评价

• 批准号: 9276240
• 负责人: DIMITRI KRAINC
• 金额: $ 55.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276240
• 关键词: Evaluation; glucocerebrosidase; pathway; biomarkers; Parkinson

PROJECT SUMMARY Parkinson disease (PD) due to monoallelic glucocerebrosidase (GBA1) gene mutations (GBA-PD) is at the forefront of novel approaches to the treatment of PD. Exciting potential therapeutic agents that target the pathway disrupted in this genetic form of PD are becoming available, and evidence suggests that benefits extend to non-mutation PD, as well. Trial development is at a pivotal stage. Demonstration of effects in trials of potential disease-modifying agents for PD in general has been impeded by uncertainty about disease etiology, heterogeneity of underlying mechanisms, few identified targets, few sensitive and stable outcome measures (especially for non-motor outcomes), and insufficient surrogate markers. This proposal aims to set the stage for clinical trials using GBA-PD as a model to transcend trial design hurdles. GBA1 mutations cause deficiency in the lysosomal glucocerebrosidase enzyme (GCase) and are the most common genetic factor associated with PD. This well-defined pathway allows study of a population with decreased heterogeneity of etiologic mechanism, and a known target for intervention. Evaluation of biochemical markers in this pathway in conjunction with clinical motor and non-motor features will provide outcome measures for clinical trials. Further, disruption of the GCase pathway may be an important representative mechanism for non-mutation, idiopathic PD (IPD), and has been implicated as a possible etiology in at least a subset of IPD. While we have cross- sectional preliminary data, validation and longitudinal assessment of these biomarkers are needed to optimize their utility in clinical trials. Unprecedented sharing of biospecimen and clinical data through the Parkinson’s Disease Biomarker Program (PDBP) enables us to leverage our extensive GBA cohort at Mount Sinai Beth Israel (MSBI). Using extant samples from our MSBI cohort, the Harvard Biomarker Study (HBS), the Parkinson’s Progression Markers Initiative (PPMI), and the PDBP, we propose to characterize focused biochemical measures of the GCase pathway, including central and peripheral biomarker assessments of enzyme, lipid and α-synuclein levels and their relation to clinical outcomes and decline. This will not only improve the likelihood of clinical trial success, but will lead to better understanding of the pathophysiologic mechanisms of this prominent etiology of PD. Specifically, we will: (Aim 1) validate findings in the MSBI dataset, associate peripheral and CSF markers, and assess their longitudinal change; (Aim 2) analytically derive a clinical severity score to optimally relate clinical and biological markers; (Aim 3) evaluate markers in IPD to discern whether a subset of IPD shares the same etiologic mechanism; and (Aim 4) evaluate RNA expression and identify genetic modifiers in extremes of GBA. Completion of these aims addressing progression and putative pharmacodynamic markers leveraging these special cohorts will provide necessary information to foster trial development and success, and expand our knowledge of the pathophysiology of GBA-PD and IPD.

项目总结 单等位基因葡萄糖脑苷酶(GBA1)基因突变所致的帕金森病(PD) 帕金森病治疗的新方法的前沿。令人兴奋的潜在治疗剂，靶向 在这种遗传形式的帕金森病中被破坏的途径正在变得可行，有证据表明，这种益处 扩展到非突变的帕金森病。试验开发正处于关键阶段。在试验中的效果演示 帕金森病潜在的疾病改良剂通常受到疾病病因的不确定性的阻碍， 潜在机制的异质性，确定的目标很少，敏感和稳定的结果衡量标准很少 (尤其是对于非运动结局)，以及替代标志物不足。这项提议的目的是为 对于使用GBA-PD作为模型的临床试验，以超越试验设计障碍。GBA1突变导致 溶酶体葡萄糖脑苷酶(GCase)缺陷是最常见的遗传因素 与帕金森病有关。这一明确的途径允许研究具有较低异质性的种群 病因机制，以及已知的干预目标。这一途径中生化标志物的评价 结合临床运动和非运动特征，将为临床试验提供结果衡量标准。此外， GCase途径的破坏可能是非突变、特发性的重要代表性机制 PD(IPD)，并已被认为是至少IPD的一个子集的可能病因。当我们有交叉的时候- 需要对这些生物标志物的断面初步数据、验证和纵向评估进行优化 它们在临床试验中的效用。通过帕金森氏症史无前例地共享生物素和临床数据 疾病生物标记计划(PDBP)使我们能够利用我们在西奈贝斯山广泛的GBA队列 以色列(MSBI)。使用我们MSBI队列中的现有样本，哈佛生物标记研究(HBS)， 帕金森进展标记物倡议(PPMI)和PDBP，我们建议表征聚焦 GCase途径的生化测量，包括中枢和外周生物标记物评估 酶、脂和α-突触核蛋白水平及其与临床结局和预后的关系。这不仅会 提高临床试验成功的可能性，但将导致对病理生理的更好理解 帕金森病的这一突出病因的机制。具体来说，我们将：(目标1)验证MSBI的调查结果 数据集，关联外周和脑脊液标记物，并评估其纵向变化；(目标2)分析 得出临床严重性评分，以最佳地关联临床和生物标记；(目标3)评估标记在 IPD以辨别IPD的子集是否具有相同的致病机制；以及(目标4)评估RNA 表达并确定GBA极端情况下的遗传修饰物。 完成这些目标，解决进展和可能的药效学标记物利用这些 特别队列将提供必要的信息，以促进试验的发展和成功，并扩大我们的 了解GBA-PD和IPD的病理生理学知识。