Mitofusin Agonists to Treat Neurodegenerative Disease

丝裂霉素激动剂治疗神经退行性疾病

基本信息

批准号：
10618385
负责人：
Gerald W. Dorn
金额：
$ 98.62万
依托单位：
MITOCHONDRIA IN MOTION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618385
关键词：
Achievement Address Affect Agonist American Amyotrophic Lateral Sclerosis Area Biochemical Biological Availability Biotechnology Brain CAG repeat Caregivers Cessation of life Charcot-Marie-Tooth Disease Chemicals Clinic Clinical Dementia Disease Disease Outcome Disease Progression Dose Etiology Experimental Models Family Frontotemporal Dementia Functional disorder Funding Genetic Genetic Diseases Genetic Risk Goals Government Grant Growth Hand Health Healthcare Hepatocyte Histologic Human Huntington Disease Impairment In Vitro Individual Injury Interruption Intervention Lead Location Manufactured Baseball Metabolism Mitochondria Modeling Morbidity - disease rate Morphology Motion Motor Neurons Movement Mus Muscle Muscle Weakness Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Neuropathy Oral Other Genetics Paralysed Pathogenicity Pathologic Pathology Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phenotype Population Positioning Attribute Process Production Program Development Psychoses Reactive Oxygen Species Research Resistance Resources Respiratory physiology Safety Schedule Small Business Technology Transfer Research Specificity Testing Therapeutic Index Time Toxic effect Universities Washington amyotrophic lateral sclerosis therapy clinical candidate commercialization experience experimental study familial amyotrophic lateral sclerosis first-in-human grasp improved in vivo injury and repair interest loss of function medical schools mitochondrial fitness mortality motility disorder mouse model nervous system disorder non-genetic novel drug class novel therapeutic intervention phase 1 study physical state pre-IND studies pre-clinical prototype repaired research and development safety study scale up screening small molecule superoxide dismutase 1 symptom treatment targeted treatment trafficking

项目摘要

Mitofusin agonists for the treatment of neurodegenerative diseases Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: A number of rare neurodegenerative diseases are characterized by mitochondrial fragmentation, dysmotility and dysfunction. Among these are Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease (HD), which cause significant morbidity and mortality in affected populations and for which there are no available disease-altering therapies. With Phase I STTR support, Mitochondria in Motion, Inc. (MiM) has developed the first pharmaceutically acceptable small molecule mitofusin activators to treat these and other neurodegenerative conditions with underlying contributory mitochondrial pathology. Mitofusin activation enhances mitochondrial fitness, metabolism and trafficking within diseased neurons, thereby improving homeostatic functioning, conferring resistance to injury and promoting neuronal repair/regrowth. During phase I we hypothesized that intervention with a mitofusin activator would have beneficial effects on etiologically diverse genetic peripheral neuropathies with a mitochondrial component. This notion was validated by phase I studies and MiM is advancing 2 pre-clinical lead mitofusin activators, CPR1-B for sustained activation in genetically heterogenous diseases like ALS and HD not caused by mitofusin (MFN) mutations, and MiM-111 for “burst” activation in Charcot-Marie- Tooth disease type 2A (CMT2A) that is directly caused by mutations in MFN2. Having identified CPR1-B as a clinical candidate in non-CMT2A neuropathies like ALS and HD, our Phase II goals are to initiate non GMP pre-IND studies positioning us for FDA IND approval (Aim 1) and define optimal CPR1-B dosing levels and schedule in ALS and HD mouse models (Aim 2). If successful we will fill an unmet healthcare need and build a commercial enterprise to serve the ~20,000 Americans with ALS and the ~150,000 Americans suffering from or at genetic risk for developing HD, their caregivers and families. Our deliverable in Phase II will be a mitofusin activator positioned for FDA IND approval and phase 1 first-in-human trials.

用于治疗神经退行性疾病的丝裂霉素激动剂杰拉尔德·多恩二世 (Gerald W Dorn II)，医学博士线粒体运动公司华盛顿大学圣路易斯医学院摘要：许多罕见的神经退行性疾病的特点是其中包括线粒体断裂、运动障碍和功能障碍。侧索硬化症 (ALS) 和亨廷顿病 (HD)，这会导致严重的受影响人群的发病率和死亡率，并且没有可用的数据在 I 期 STTR 支持下，Mitochondria in Motion, Inc. (MiM) 开发出第一个药学上可接受的小分子线粒体融合蛋白激活剂来治疗这些和其他具有潜在作用的神经退行性疾病贡献性线粒体病理学。患病神经元内的健康、新陈代谢和运输，从而改善稳态功能，赋予对损伤的抵抗力并促进神经元在第一阶段，我们用线粒体融合蛋白进行了干预。激活剂将对病因多样的遗传外周产生有益的影响具有线粒体成分的神经病这一概念得到了第一阶段的验证。研究和 MiM 正在推进 2 种临床前先导线粒体融合蛋白激活剂 CPR1-B 遗传异质性疾病（如 ALS 和 HD）的持续激活并非引起通过线粒体融合素 (MFN) 突变和 MiM-111 在 Charcot-Marie 中“爆发”激活由 MFN2 突变直接引起的 2A 型牙齿疾病 (CMT2A)。确定 CPR1-B 是治疗 ALS 和 HD 等非 CMT2A 神经病的临床候选药物，我们的 II 期目标是启动非 GMP IND 前研究，为 FDA IND 做好准备批准（目标 1）并定义 ALS 和 HD 中的最佳 CPR1-B 剂量水平和时间表小鼠模型（目标 2）。如果成功，我们将填补未满足的医疗保健需求并建立一个商业企业为约 20,000 名患有 ALS 的美国人和约 150,000 名患有 ALS 的美国人提供服务患有 HD 或有罹患 HD 遗传风险的美国人、他们的照顾者和我们在第二阶段的交付成果将是一种用于 FDA IND 的线粒体融合蛋白激活剂。批准和第一阶段首次人体试验。