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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：帕金森病 (PD) 病理学的特征是神经元内包涵体的形成，称为路易体 (LB) 和路易神经突 (LN)，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阻止天然/单体形式的 α-syn 聚集来减少这些有毒聚集物。帕金森病需要新的、有效的疾病缓解疗法尽管抗抑郁药已被证明对帕金森病抑郁症是安全有效的，但这些药物对疾病进展的影响仍然未知。然而，我们实验室之前的工作表明。三环类抗抑郁药 (TCA) 在临床前毒素模型（Paumier 等人，2014 年）和早期 PD 患者队列数据的回顾性分析中（Paumier 等人，2014 年）均能减缓疾病进展。将这些发现和其他发现结合起来（Jeannotte 等人，2009a，Jeannotte 等人，2009b，Trushina 等人，2009，Chung 等人，2010，Chadwick 等人，2011，Zschocke 等人，2011），Valera 等人，2014），支持这一观点抗抑郁药在现有的安全框架内具有缓解疾病的潜力。拟议研究的目的是确定 NOR 是否可以成为缓解 PD 疾病的治疗方法。我们将检验我们的中心假设，即 NOR 会减弱 α 的积累/聚集。 -syn 发生在 PD 中，导致黑质纹状体保留。我们的假设是根据我们自己的初步发现制定的，即 NOR 是体外和体内 α-syn 聚集的有效抑制剂。拟议研究的基本原理与无法评估临床中 α-syn 靶点的参与度有关，并且随后无法将神经生物学变化与前瞻性临床试验所需的靶点参与度直接联系起来，我们建议进一步开发。通过以下方式确定 NOR 的临床使用情况：1.) 在非人类灵长类动物中进行测试，以及 2.) 从参与正在进行的帕金森病进展标记计划 (PPMI) 临床试验的受试者中挖掘数据，我们预测 NOR 能够降低帕金森病进展标记物计划 (PPMI) 临床试验的能力。 α-syn 聚集率将防止与 LB 样病理学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。