MITOFUSIN AGONISTS TO TREAT NEURODEGENERATIVE DISEASE

线粒体融合蛋白激动剂治疗神经退行性疾病

基本信息

批准号：
10290982
负责人：
Gerald W. Dorn
金额：
$ 7.85万
依托单位：
MITOCHONDRIA IN MOTION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10290982
关键词：
Affect Agonist American Amyotrophic Lateral Sclerosis Biotechnology Caregivers Cells Cessation of life Charcot-Marie-Tooth Disease Data Disease Disease Outcome Disease Progression Drug Kinetics FDA approved Family Feasibility Studies Future Genetic Genetic Risk Healthcare Huntington Disease Individual Intervention Investigation Lead Manufactured Baseball Metabolism Mitochondria Modeling Morbidity - disease rate Motion Muscle Weakness Muscular Atrophy Mutation Neurodegenerative Disorders Other Genetics Paralysed Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase Population Property Proteins Publishing Rare Diseases Small Business Technology Transfer Research Universities Validation Washington blood-brain barrier penetration effective therapy first-in-human humanized mouse improved in vivo medical schools mitochondrial dysfunction mitochondrial fitness mortality mouse model novel drug class pre-clinical response to injury small molecule trafficking validation studies

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: There are a number of rare neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease (HD), for which there is no available or effective therapy and which lead to significant morbidity and mortality in affected populations. Mitochondria in Motion, Inc. will develop and produce investigational first-in-class small molecule mitofusin agonists, under an FDA approved IND, to treat these conditions. Mitofusin agonists enhance mitochondrial fitness, metabolism, and trafficking within cells, thus improving homeostatic functioning and injury-responses of cells adversely impacted by genetic mitochondrial dysfunction. Our published disease focus for mitofusin agonists was Charcot-Marie-Tooth disease type 2A, caused by mutations in our drug’s protein target, Mitofusin 2. Here, we hypothesized that intervention with a mitofusin agonist would have beneficial effects on other genetic peripheral neuropathies with a mitochondrial component, which is supported by our preclinical data in ALS and HD patient-derived cells. Thus, 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. In this Phase I STTR we propose to optimize the pharmacokinetic properties of mitofusin agonists for systemic administration and blood-brain-barrier penetration (Aim 1), and complete in vivo feasibility and validation studies of mitofusin agonists to delay disease progression in the well characterized SOD1G93A mouse model of ALS. Our deliverable in Phase I will be a mitofusin agonist(s) ready for STTR Phase II IND-enabling studies and validation in an expanded number of orphan diseases, to prepare for future 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：有许多罕见的神经退行性疾病，包括肌萎缩侧索硬化症。硬化症 (ALS) 和亨廷顿病 (HD)，目前尚无可用或有效的治疗方法并导致受影响人群中线粒体的显着发病率和死亡率。 Inc. 将开发和生产研究中的一流小分子线粒体融合蛋白激动剂， FDA 批准了 IND，用于治疗这些疾病，Mitofusin 激动剂可增强线粒体健康。新陈代谢和细胞内运输，从而改善稳态功能和损伤反应我们发表的疾病重点是受遗传线粒体功能障碍影响的细胞。丝裂霉素激动剂是 2A 型腓骨肌萎缩症，由我们药物的突变引起蛋白质靶点，线粒体融合蛋白 2。在这里，我们寻求使用线粒体融合蛋白激动剂进行干预对其他具有线粒体成分的遗传性周围神经病有有益的影响，我们在 ALS 和 HD 患者来源的细胞中的临床前数据支持了这一点。因此，我们将填写。未满足的医疗保健需求，并建立一家商业企业，为约 20,000 名美国人提供服务 ALS 和约 150,000 名患有 HD 或有罹患 HD 遗传风险的美国人及其护理人员在第一阶段 STTR 中，我们建议优化其药代动力学特性。用于全身给药和血脑屏障渗透的丝裂霉素激动剂（目标 1），以及完成线粒体融合蛋白激动剂延缓疾病进展的体内可行性和验证研究我们在第一阶段的交付成果将是一个经过充分表征的 ALS SOD1G93A 小鼠模型。丝裂霉素激动剂已准备好进行 STTR II 期 IND 支持研究和扩大验证一些罕见疾病，为未来的首次人体试验做好准备。