Nortriptyline-mediated attenuation of alpha-synuclein pathology in Parkinson's disease

去甲替林介导的帕金森病α-突触核蛋白病理学减弱

• 批准号: 9763677
• 负责人: Timothy J. Collier
• 金额: $ 43.25万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763677
• 关键词: Amitriptyline; Antidepressive Agents; Attenuated; Behavior; Binding; Biological; Biological Assay; Blood; Brain; Clinic; Clinical; Clinical Data; Clinical Trials; Cognitive; Data; Data Analyses; Disease; Disease Progression; Dopamine; Dose; Enrollment; FDA approved; Functional disorder; Goals; Histology; Human; Image; Immunotherapy; In Vitro; Kinetics; Laboratories; Lewy Bodies; Link; Manuscripts; Measures; Mediating; Mental Depression; Modeling; Neurites; Neurobiology; Newly Diagnosed; Nortriptyline; Outcome; Outcome Measure; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Preparation; Prevention; Primates; Process; Rattus; Research; Retrospective Studies; Role; Safety; Serum; Testing; Therapeutic; Time; Toxin; Tricyclic Antidepressive Agents; Work; alpha synuclein; attenuation; base; clinical biomarkers; cohort; data mining; dopamine transporter; dose information; in vivo; indexing; inhibitor/antagonist; nonhuman primate; novel; potential biomarker; pre-clinical; preservation; prevent; primary endpoint; prospective; public health relevance; rate of change; secondary outcome; single photon emission computed tomography; synucleinopathy; targeted biomarker; transmission process

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) pathology is characterized by the formation of intraneuronal inclusions called Lewy bodies (LBs) and Lewy Neurites (LNs), that are comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One therapeutic strateg to slow disease progression is to reduce these toxic aggregates by preventing the native/monomeric form of α-syn from aggregating. There is substantial need for new, efficacious disease-modifying therapies in PD. Despite the fact that antidepressants have already been shown to be safe and efficacious for depression in PD, the effects of these drugs on disease progression remain unknown. However, previous work from our laboratory suggests tricyclic antidepressants (TCAs) slow disease progression in both preclinical toxin models (Paumier et al., 2014) and in a retrospective analysis of data from an early cohort of patients with PD (Paumier et al., 2012). Together these findings, and others (Jeannotte et al., 2009a, Jeannotte et al., 2009b, Trushina et al., 2009, Chung et al., 2010, Chadwick et al., 2011, Zschocke et al., 2011, Valera et al., 2014), support the notion that antidepressants have disease-modifying potential within an existing framework of established safety. The objective of the proposed studies is to determine whether NOR can be a disease- modifying treatment for PD. We will test our central hypothesis that NOR attenuates the accumulation/aggregation of α-syn that occurs in PD, resulting in nigrostriatal preservation. Our hypothesis has been formulated on the basis of our own preliminary findings that NOR is a potent inhibitor of α-syn aggregation in vitro and in vivo. Rationale for the proposed studies is related to the inability to assess engagement of the α-syn target in the clinic and subsequently link neurobiological changes directly to improvement. Absent a clinical biomarker for target engagement desirable for a prospective clinical trial, we propose to further develop the case for clinical use of NOR by: 1.) testing in nonhuman primates, and 2.) mining data from subjects enrolled in the ongoing Parkinson's Progressive Marker Initiative (PPMI) clinical trial. We predict that the capacity of NOR to reduce the rate of�-syn aggregation will prevent the spread and resulting dysfunction associated with LB-like pathology and this prevention of aggregation will be correlated with neurobiological benefit.

 描述（由申请方提供）：帕金森病（PD）病理学特征为形成称为路易体（LB）和路易神经突（LN）的神经元内包涵体，主要由错误折叠的纤维状α-突触核蛋白（α-syn）组成。减缓疾病进展的一种治疗策略是通过防止α-syn的天然/单体形式聚集来减少这些毒性聚集体。在PD中存在对新的、有效的疾病修饰疗法的实质性需求。尽管抗抑郁药已被证明对PD患者的抑郁症安全有效，但这些药物对疾病进展的影响仍然未知。然而，来自我们实验室的先前工作表明三环抗抑郁药（TCA）在两种临床前毒素模型中减缓疾病进展（Paumier等人，2014）和来自早期PD患者队列的数据的回顾性分析（Paumier等人，2012年）。这些发现和其他发现一起（Jeannotte等人，2009 a，Jeannotte等人，2009 b，Trushina等人，2009年，Chung等人，2010年，Chadwick等人，2011年，Zschocke等人，2011年，瓦莱拉等人，2014），支持抗抑郁药在现有安全性框架内具有疾病修饰潜力的概念。拟定研究的目的是确定NOR是否可以作为PD的疾病改善治疗。我们将检验我们的中心假设，即NOR减弱PD中发生的α-syn的积累/聚集，导致黑质纹状体保留。我们的假设是基于我们自己的初步发现，即NOR是体外和体内α-syn聚集的有效抑制剂。拟定研究的依据与无法评估α-syn靶点在临床中的作用以及随后将神经生物学变化与改善直接联系起来有关。由于缺乏前瞻性临床试验所需的靶点接合的临床生物标志物，我们建议通过以下方式进一步开发NOR临床使用的情况：1.在非人灵长类动物中测试，以及2.）从正在进行的帕金森病进展标志物倡议（PPMI）临床试验中招募的受试者中挖掘数据。我们预测NOR降低β-syn聚集速率的能力将防止与LB样病理相关的扩散和由此产生的功能障碍，并且这种聚集的预防将与神经生物学益处相关。