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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：
9925848
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/9925848
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 Obesity 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 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 pre-clinical prevent 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.

我们建议测试的方法，重点从压力反应转移到压力弹性，和设施，神经保护治疗过程，可作为神经退行性疾病的有效治疗，如HD的命令。我们证明，部分抑制线粒体复合物I的活性与小摩尔- 我们实验室开发的cules诱导了多种应激恢复机制，这些机制与机制重叠，长寿的秘诀这些小分子穿透血脑屏障并在线粒体中积累其中它们部分抑制线粒体复合物I的活性。对这种轻微压力的适应性反应- 导致激活诱导抗氧化应激保护的分子机制，增强细胞能量，恢复轴突运输和保护突触的完整性和功能，是的。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、喂食高脂肪饮食的野生型小鼠以及人类神经元和纤维蛋白中，来自AD和线粒体疾病患者的原始细胞。在小鼠神经元中表达截短和全长的突变亨廷顿蛋白（mHtt）蛋白，用部分复合物I抑制剂处理显著降低mHtt聚集。恢复改变的胆固醇稳态和内吞作用。在R6/2小鼠中，这种治疗延长了存活，减少扣抱表型和癫痫发作。我们的最终目标是开发一种疾病- HD的改良治疗。本提案的目标是建立概念验证，即标准件的应用- TAL复合物I抑制剂在HD的人类和小鼠模型中提供神经保护作用，神经保护的关键分子机制。基于我们的初步数据和线粒体- al功能障碍和氧化应激增加有助于HD机制，我们建议验证一个假设部分复合物I抑制剂的应用可以延缓HD的发病和发展，通过改善线粒体动力学和功能以及增加对氧化应激的抵抗，应力具体的实验目的是：1）研究慢性给药是否能降低线粒体的部分复合物I抑制剂延迟细菌人工染色体HD中HD的发生和发展（BACHD）转基因小鼠;（2）确定雄性和雌性中的最佳治疗机会窗口 BACHD小鼠;（3）建立不同浓度下参与神经保护的分子机制的层次结构，疾病的阶段;（4）证明使用人HD细胞的这种方法的翻译潜力。拟议的研究基于强有力的前提，并将使用INNO对假设进行严格的检验。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。这些结果将提供关键的生物学证据，以确定合理性和预处理。临床标准，以支持进一步临床开发用于HD的特异性线粒体复合物I抑制剂治疗自从专利的部分复合物I抑制剂作为一类疾病修饰剂的开发以来，神经退行性疾病的策略目前在我们实验室处于领先优化的高级阶段，这一建议的结果可以证明这一新战略的应用，从发现到临床应用的时间。