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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.

摘要