Evaluation of glucocerebrosidase pathway biomarkers in Parkinson Disease

项目摘要 单等位基因葡萄糖脑苷脂酶（GBA 1）基因突变（GBA-PD）引起的帕金森病（PD）是 治疗PD的新方法的最前沿。激发潜在的治疗剂，靶向 在这种遗传形式的PD中被破坏的通路正在变得可用，证据表明， 非突变PD也是如此。试验开发正处于关键阶段。试验中的效果证明 用于PD的潜在疾病调节剂通常受到疾病病因学不确定性的阻碍， 潜在机制的异质性，确定的靶点很少，敏感和稳定的结局指标很少 （特别是对于非运动结果），以及替代标记物不足。这一提议旨在为 用于使用GBA-PD作为模型的临床试验，以超越试验设计障碍。GBA 1突变导致 溶酶体葡萄糖脑苷脂酶（GCase）缺乏，是最常见的遗传因素 与PD有关。这种明确的途径允许研究具有降低的异质性的群体， 病因机制和已知的干预目标。在这一途径中的生化标志物的评估， 结合临床运动和非运动特征将为临床试验提供结果测量。此外，本发明还 GCase途径的破坏可能是非突变性、特发性和非特异性的一个重要的代表性机制。 PD（IPD），并已被认为是至少一个IPD子集的可能病因。当我们交叉- 需要对这些生物标志物进行截面初步数据、验证和纵向评估， 它们在临床试验中的效用。通过帕金森氏症前所未有地共享生物标本和临床数据 疾病生物标志物计划（PDBP）使我们能够利用我们在西奈山贝丝广泛的GBA队列 以色列（MSBI）。使用来自我们MSBI队列的现存样本，哈佛生物标志物研究（HBS）， 帕金森病进展标志物倡议（PPMI）和PDBP，我们建议将重点 GCase途径的生化指标，包括中枢和外周生物标志物评估， 酶、脂质和α-突触核蛋白水平及其与临床结局和下降的关系。这不仅会 提高临床试验成功的可能性，但将导致更好地了解病理生理学 这一突出的PD病因机制。具体而言，我们将：（目标1）验证MSBI中的发现 数据集，关联外周和CSF标志物，并评估其纵向变化;（目的2）分析 导出临床严重性评分以最佳地关联临床和生物学标志物; IPD以辨别IPD的子集是否具有相同的病因机制;以及（目的4）评估RNA 表达和鉴定极端GBA中的遗传修饰剂。 完成这些目标，解决进展和利用这些目标的推定药效学标志物 特殊的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。

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.