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Small molecule mitochondria-targeted therapeutics for Huntingtons Disease

亨廷顿病的小分子线粒体靶向疗法

基本信息

批准号：
10160973
负责人：
Eugenia Trushina
金额：
$ 53.51万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160973
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Autophagocytosis Axon Bacterial Artificial Chromosomes Behavior Biochemistry Biogenesis Biological Biological Models Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Caloric Restriction Cells Cellular biology Cholesterol Homeostasis Chronic Chronology Code Complex Corpus striatum structure Data Development Diabetes Mellitus Disease Disease model Elderly Endocytosis Evaluation FDA approved Female Fibroblasts Functional disorder Genetic Goals Health High Fat Diet Homeostasis Human Huntington Disease Huntington gene Huntington protein Imaging Techniques Inflammation Laboratories Length Lipids Longevity Metabolic Metformin Mitochondria Mitochondrial Diseases Molecular Mus Names Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Oxidative Phosphorylation Oxidative Stress Paper Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Population Process Proteins Pyrones Resistance Resveratrol Safety Seizures Stress Synapses Systems Biology Techniques Testing Therapeutic Time Transgenic Mice Translations Treatment Efficacy Wild Type Mouse aged base biological adaptation to stress clinical application clinical development cognitive function cohort effective therapy efficacy evaluation gene therapy human model improved in vivo inhibitor/antagonist innovation insight lead optimization male mitochondrial DNA mutation mitochondrial dysfunction mouse model multimodality mutant neuron loss neuroprotection novel therapeutic intervention obesity prevention pre-clinical response restoration small molecule stress resilience synaptic function targeted treatment trafficking

项目摘要

We propose to test the approach that shifts the focus from stress response to stress resilience, and the facilita- tion of neuroprotective therapeutic processes that may serve as effective treatment in neurodegenerative dis- orders such as HD. We demonstrated that partial inhibition of mitochondrial complex I activity with small mole- cules developed in our laboratory induces multiple mechanisms of stress resilience that overlap with mecha- nisms of longevity. These small molecules penetrate the blood brain barrier and accumulate in mitochondria where they partially inhibit the activity of mitochondrial complex I. The adaptive response to this mild stress re- sults in the activation of molecular mechanisms that induce a protection against oxidative stress, the en- hancement of cellular energetics, restoration of axonal trafficking and protection of synaptic integrity and func- tion. Neuroprotection using these strategy was confirmed in multiple mouse models of Alzheimer's Disease (AD), chronologically aged mice, in wild type mice fed with a high fat diet, and in human neurons and fibro- blasts from patients with AD and mitochondria disease. In mouse neurons expressing truncated and full-length mutant Huntingtin (mHtt) protein, treatment with partial complex I inhibitors significantly reduced mHtt aggrega- tion, restored altered cholesterol homeostasis and endocytosis. In R6/2mice, this treatment extended the sur- vival, and reduced clasping phenotype and incidents of seizures. Our ultimate goal is to develop a disease- modifying treatment for HD. Objectives of this proposal are to establish proof of concept that application of par- tial complex I inhibitors provides neuroprotection in human and mouse models of HD, and to gain the insight in critical molecular mechanisms of neuroprotection. Based on our preliminary data and the fact that mitochondri- al dysfunction and increased oxidative stress contribute to HD mechanism, we propose to test a hypothesis that application of partial complex I inhibitors could delay the onset and development of HD and protect against neuronal loss by improving mitochondrial dynamics and function and increasing the resistance to oxidative stress. The specific experimental goals are: 1) to investigate whether chronic administration of mitochondrial partial complex I inhibitor delays the onset and development of HD in bacterial artificial chromosome HD (BACHD) transgenic mice; (2) to determine the best window of therapeutic opportunity in male and female BACHD mice; (3) to establish the hierarchy of molecular mechanisms involved in neuroprotection at different stages of the disease; (4) to demonstrate the translational potential of this approach using human HD cells. The proposed studies are based on strong premise and will provide rigorous test of the hypothesis using inno- vative cell biology, biochemistry, systems biology and imaging techniques, and pharmacological and genetic interventions. The outcomes will provide the critical biological evidence to establish the rationale and the pre- clinical criteria, to support further clinical development of specific mitochondrial complex I inhibitors for HD treatment. Since the development of proprietary partial complex I inhibitors as a first in class disease modifying strategy for neurodegenerative diseases is currently in advanced stage of lead optimization in our laboratory, the outcomes of this proposal could justify the application of this new strategy for HD significantly shortening the time from the discovery to the clinical application in humans.

我们建议测试将重点从压力反应转移到压力恢复的方法，以及便利性神经保护治疗过程可能作为神经退行性疾病的有效治疗订单如高清。我们证明了小摩尔分子对线粒体复合物 I 活性的部分抑制我们实验室开发的 cules 诱导了多种与机械重叠的应激恢复机制。长寿主义。这些小分子穿透血脑屏障并在线粒体中积累它们部分抑制线粒体复合物 I 的活性。对这种轻微应激的适应性反应重新导致分子机制的激活，诱导针对氧化应激的保护，增强细胞能量、恢复轴突运输以及保护突触完整性和功能。使用这些策略的神经保护作用在多种阿尔茨海默病小鼠模型中得到证实（AD），按时间顺序老化的小鼠，在高脂肪饮食喂养的野生型小鼠中，以及在人类神经元和纤维中来自 AD 和线粒体疾病患者的原始细胞。在表达截短和全长的小鼠神经元中突变亨廷顿 (mHtt) 蛋白，用部分复合物 I 抑制剂治疗显着减少 mHtt 聚集化，恢复改变的胆固醇稳态和内吞作用。在 R6/2 小鼠中，这种治疗延长了活力，并减少紧握表型和癫痫发作事件。我们的最终目标是发展一种疾病—— 修改 HD 的治疗方法。该提案的目标是建立概念证明，即应用par- 复合物 I 抑制剂在人类和小鼠 HD 模型中提供神经保护，并深入了解神经保护的关键分子机制。根据我们的初步数据和线粒体的事实功能障碍和氧化应激增加导致 HD 机制，我们建议检验一个假设部分复合物I抑制剂的应用可以延缓HD的发生和发展并预防通过改善线粒体动力学和功能并增加对氧化的抵抗力来减少神经元损失压力。具体实验目标是：1）研究长期给予线粒体是否部分复合物I抑制剂延缓细菌人工染色体HD中HD的发生和发展 (BACHD)转基因小鼠； (2)确定男性和女性的最佳治疗机会窗口 BACHD小鼠； (3) 建立不同程度神经保护作用分子机制的层次结构疾病的阶段； (4) 使用人类 HD 细胞证明该方法的转化潜力。拟议的研究基于强有力的前提，并将使用创新对假设进行严格的检验原生细胞生物学、生物化学、系统生物学和成像技术、药理学和遗传学干预措施。结果将提供关键的生物学证据来确定理由和预临床标准，支持 HD 特异性线粒体复合物 I 抑制剂的进一步临床开发治疗。自从开发出专有的部分复合物 I 抑制剂作为一流的疾病修饰药物以来神经退行性疾病策略目前在我们的实验室处于先导物优化的高级阶段，该提案的结果可以证明应用这一新策略的合理性，以显着缩短 HD 从发现到人类临床应用的时间。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comprehensive protocol for multiplatform metabolomics analysis in patient-derived skin fibroblasts.

DOI：
10.1007/s11306-019-1544-z
发表时间：
2019-05-23
期刊：
Metabolomics : Official journal of the Metabolomic Society
影响因子：
0
作者：
Wilkins J;Sakrikar D;Petterson XM;Lanza IR;Trushina E
通讯作者：
Trushina E

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.

DOI：
10.3233/jad-201015
发表时间：
2021
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
0
作者：
Stojakovic A;Chang SY;Nesbitt J;Pichurin NP;Ostroot MA;Aikawa T;Kanekiyo T;Trushina E
通讯作者：
Trushina E