Small Molecule Mitochondria-Targeted Therapeutics for AD

小分子线粒体靶向治疗 AD

基本信息

批准号：
10576450
负责人：
Eugenia Trushina
金额：
$ 77.84万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10576450
关键词：
APP-PS1 Abeta synthesis Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Binding Biochemical Biochemistry Biogenesis Biological Assay Biological Availability Biological Markers Blinded Blood Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Caloric Restriction Cell Differentiation process Chemicals Chemistry Chronology Clinic Clinical Clinical Investigator Clinical Trials Cognitive Competitive Binding Complex Computational Biology Data Data Discovery Dendritic Spines Development Disease Disease Progression Documentation Dose Ensure Evaluation Exercise Exhibits Fibroblasts Flavin Mononucleotide Formulation Freedom Functional disorder Goals Grant High Fat Diet Homeostasis Human In Vitro Individual Inflammation Infrastructure Investigation Investigational Drugs Investigational New Drug Application Laboratories Lead Legal patent Long-Term Potentiation Lymphocyte Measures Meta-Analysis Methodology Mitochondria Molecular Molecular Target Mus Nerve Degeneration Neurons Oral Outcome Oxidation-Reduction Oxidative Stress Pamphlets Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology Phase I Clinical Trials Play Positron-Emission Tomography Preparation Prevention Probability Process Production Property Protein Kinase Proteins Reporting Research Research Personnel Resistance Resources Risk Safety Series Signal Transduction Specificity Stream Structure-Activity Relationship Synapses System Systems Biology Testing Therapeutic Time Toxic effect Transgenic Mice Translations Validation Variant Wild Type Mouse Work Writing aged base cognitive function drug candidate effective therapy efficacy study familial Alzheimer disease fluorodeoxyglucose glucose uptake glycogen synthase kinase 3 beta improved in vivo in vivo evaluation induced pluripotent stem cell inhibitor lead optimization lead series mouse model neuroprotection next generation novel novel strategies pre-clinical preclinical development preclinical study prevent response scale up screening small molecule small molecule therapeutics success targeted biomarker targeted treatment transcriptome sequencing translational potential translational study translational therapeutics

项目摘要

Abstract Abnormal energy homeostasis in Alzheimer’s Disease (AD) is associated with synaptic dysfunction and neurodegeneration. Emerging data generated using multiple systems biology approaches and meta-analysis in AD patients identified an AMP-protein kinase (AMPK) integrated signaling network that operates down stream of mitochondrial energy production and could provide neuroprotection in AD. We show that partial inhibition of mitochondrial complex I (MCI) improves glucose uptake and utilization, dendritic spine maturation, long-term potentiation, synaptic activity, cognitive function, and reduces Aβ and pTau accumulation, oxidative stress and inflammation resulting in neuroprotection in pre- and symptomatic preclinical mouse models of AD and aging. These studies suggest that novel strategies to alter mitochondrial energy homeostasis may have profound translational therapeutic potential for AD. Using multiple biochemistry, computational and systems biology approaches, and extensive in vivo translational studies, we developed small molecules that bind next to the flavin mononucleotide redox center of MCI mildly inhibiting its activity. The molecular mechanism of MCI inhibitors impinges on pathways induced by caloric restriction and exercise including activation of AMPK; increased resistance to oxidative stress; enhanced mitochondrial biogenesis, energetics, dynamics and function; reduction of glycogen synthase kinase 3β activity; increased levels of brain-derived neurotrophic factor (BDNF) and synaptic proteins in vivo; a reduction in levels of Aβ and pTau and inflammation ultimately blocking neurodegeneration in AD mice. We have confirmed these effects in a range of systems (primary mouse neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, chronologically aged mice, mitochondria isolated from mouse and human brain, human lymphocytes, fibroblasts and neuronal cells differentiated from human iPSCs), supporting the high translational potential of this approach. The advantages of our molecules include the ability to penetrate the blood brain barrier, low toxicity, in vivo efficacy, and the known molecular target. Based on the target validation and the identification of the molecular mechanism, we developed multiple in vitro and in vivo assays that were used for structure-activity relationship (SAR) studies resulting in the development of a robust Discovery Funnel and arrays of novel series of proprietary compounds MCI inhibitors with promising drug-like properties (US patent granted). We propose to advance our small molecule therapeutics to the clinic by entering the BPN at the Discovery stage where, with the team of the BPN Consultants and CROs, we will progress toward the identification of preclinical and development candidates, and to the submission of the IND application in preparation for a Phase I Clinical Trial.

抽象的阿尔茨海默氏病（AD）中能量稳态异常与突触功能障碍和神经变性。使用多种系统生物学方法和荟萃分析生成的新兴数据在AD患者中，鉴定出一个AMP-蛋白激酶（AMPK）的集成信号网络，该信号网络下降线粒体能量产生的流，可以在AD中提供神经保护。我们表明那部分线粒体复合物I（MCI）的抑制可改善葡萄糖摄取和利用，树突状脊柱成熟，长期增强，突触活性，认知功能并降低Aβ和PTAU积累，氧化在AD的临床前和有症状的临床前小鼠模型中导致神经保护的压力和注射和老化。这些研究表明，改变线粒体能量稳态的新型策略可能具有 AD的深刻翻译治疗潜力。使用多种生物化学，计算和系统生物学方法和广泛的体内翻译研究，我们开发了与接下来结合的小分子到MCI的黄素单核苷酸氧化还原中心轻度抑制其活性。 MCI的分子机制抑制剂会影响热量限制和运动引起的途径，包括激活AMPK；增加对氧化应激的耐药性；线粒体生物发生，能量，动力学和增强功能;糖原合酶激酶3β活性的降低；脑衍生的神经营养水平增加因子（BDNF）和体内突触蛋白；最终Aβ和PTAU和炎症的水平降低阻止AD小鼠的神经变性。我们已经在一系列系统中确认了这些效果（主要小鼠神经元，多种家庭AD的小鼠模型，用高脂肪饮食喂养的野生型小鼠，按时间顺序老年小鼠，从小鼠和人脑，人淋巴细胞，成纤维细胞和神经元分离的线粒体细胞与人IPSC区分开），支持这种方法的高转化潜力。分子的优势包括渗透血脑屏障，低毒性的能力，体内功效和已知的分子靶标。基于目标验证和分子靶标的识别。机制，我们开发了用于结构活性关系的多个体外和体内测定（SAR）导致发展鲁棒的发现漏斗和一系列新颖系列的研究专有化合物具有有前途的药物样特性（授予美国专利）的MCI抑制剂。我们建议通过在发现阶段进入BPN，将我们的小分子疗法推向诊所 BPN顾问和CRO的团队，我们将朝着临床前的识别和开发候选人，并提交IND申请以准备I期临床审判。