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：
9137744
负责人：
Timothy J. Collier
金额：
$ 57.61万
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137744
关键词：
Amitriptyline Antidepressive Agents Attenuated Behavior Binding Biological Biological Assay Biological Preservation Blood Brain Clinic Clinical Clinical Data Clinical Trials Cognitive Data Data Analyses Disease Disease Progression Dopamine Dose Enrollment FDA approved Functional disorder Goals Health 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 Pathology Patients Pharmaceutical Preparations Phenotype Preparation Prevention Primates Process Rattus Research Retrospective Studies Role Safety Serum Staging Testing Therapeutic Time Toxin Tricyclic Antidepressive Agents Work alpha synuclein attenuation base clinical biomarkers cohort data mining dopamine transporter in vivo indexing inhibitor/antagonist nonhuman primate novel potential biomarker pre-clinical prevent prospective rate of change secondary outcome single photon emission computed tomography synucleinopathy 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（由适用提供）：帕金森氏病（PD）病理学的特征是形成了称为Lewy身体（LBS）和Lewy神经突（LNS）的神经内包含物，这些含量为主要折叠，纤维纤维α-核蛋白（α-syn）。慢慢疾病进展的一种理论策略是通过防止α-Syn的天然/单体形式的聚集来减少这些有毒骨料。在PD中，需要新的，有效的疾病改良疗法。尽管已经证明抗抑郁药对PD的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，我们实验室的先前工作表明，在临床前毒素模型中，三环抗抑郁药（TCAS）缓慢疾病进展（Paumier等人，2014年）以及对PD患者早期的数据的回顾性分析（Paumier等人，2012年）。 Together these findings, and others (Jeannotte et al., 2009a, Jeannotte et al., 2009b, Trumpina 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.拟议研究的目的是确定是否可以对PD进行疾病的治疗方法。我们将检验我们的中心假设，即在PD中发生的α-Syn的积累/聚集也不会导致鼻叶。我们的假设是根据我们自己的初步发现提出的，即体外和体内的α-Syn聚集的潜在抑制剂也不是。拟议的研究的基本原理与无法评估α-Syn靶标在临床中的参与度有关，并随后将神经生物学变化直接联系起来与改善联系在一起。缺乏对前瞻性临床试验的临床生物标志物进行靶向参与的临床生物标志物，我们建议进一步开发NOR的临床使用案例：1。）在非人类隐私中进行测试，以及2.）从正在进行的Parkinson的帕克森（Parkinson）渐进式标记启动（PPMI）临床试验中的受试者中挖掘数据。我们预测，降低SYN聚集速率的能力将防止与LB样病理相关的扩散和功能障碍，并且这种预防聚集将与神经生物学益处相关。