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

• 批准号: 10020801
• 负责人: Gerald W. Dorn
• 金额: $ 22.47万
• 依托单位: MITOCHONDRIA IN MOTION, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020801
• 关键词: Adult; Affect; Agonist; American; Amyotrophic Lateral Sclerosis; Animal Model; Biological Availability; Biotechnology; Blinded; Brain; Capital Financing; Caregivers; Caring; Cells; Cessation of life; Charcot-Marie-Tooth Disease; Chemicals; Chorea; Confocal Microscopy; Controlled Study; Data; Disabled Persons; Disease; Disease Outcome; Disease Progression; Drug Kinetics; FDA approved; Family; Family Caregiver; Feasibility Studies; Fibroblasts; Funding; Future; Generations; Genetic; Genetic Diseases; Genetic Risk; Goals; Healthcare; Hour; Huntington Disease; In Vitro; Individual; Intervention; Intramuscular; Investigation; Investigational Drugs; Lead; Locomotion; Longevity; Manufactured Baseball; Metabolism; Mitochondria; Modeling; Modification; Morbidity - disease rate; Motion; Mus; Muscle Weakness; Muscular Atrophy; Mutation; Nerve; Nerve Degeneration; Nerve Regeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Onset of illness; Orphan Drugs; Other Genetics; Paralysed; Pathology; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Plasma; Population; Preparation; Property; Proteins; Publishing; Randomized; Rare Diseases; Resources; Rilutek; Risk; Rotarod Performance Test; Safety; Small Business Technology Transfer Research; Symptoms; Technology; Testing; Therapeutic; Toxic effect; Universities; Validation; Washington; biomarker identification; blood-brain barrier penetration; commercialization; disability; effective therapy; efficacy testing; field study; first-in-human; fitness; humanized mouse; improved; in vivo; medical schools; mitochondrial dysfunction; mitochondrial fitness; mortality; mouse model; nerve conduction study; neuromuscular; neuromuscular function; neuron loss; novel drug class; peptidomimetics; pharmacophore; pre-clinical; preclinical efficacy; prevent; programs; regenerative; repaired; response to injury; small molecule; symptom treatment; trafficking; validation studies

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.

丝线激动剂治疗神经退行性疾病 Gerald W Dorn II，医学博士 线粒体运动公司 圣路易斯医学院华盛顿大学 摘要：有许多罕见的神经退行性疾病，包括 肌萎缩性侧索硬化症（ALS）和亨廷顿氏病（HD），其中有 没有可用或有效的疗法，可以导致明显的发病率和死亡率 受影响的人群。线粒体In Motion，Inc。将开发和生产 在FDA批准下，研究性的第一类小分子丝线激动剂激动剂 印度，治疗这些条件。线粒体激动剂增强线粒体适应性， 新陈代谢和细胞中的贩运，从而改善了稳态功能和 细胞的损伤反应受到遗传线粒体功能障碍的不利影响。我们的 麦托法辛激动剂的发表疾病重点是charcot-marie-tooth疾病类型 2a，是由我们药物蛋白靶标的突变引起的，丝线曲霉素2。在这里，我们 假设用丝线激动剂的干预对 其他有线粒体成分的遗传周围神经病，这是 在ALS和HD患者衍生细胞中的临床前数据支持。那我们将填补 未满足的医疗保健需求并建立商业企业，为约20,000 ALS的美国人和约有15万名美国人患有或有遗传风险 发展高清，他们的照顾者和家庭。在这个阶段，我建议 优化丝线激动剂的药代动力学特性 给药和血脑屏障渗透（AIM 1），并在体内完成 丝线激动剂延迟疾病进展的可行性和验证研究 ALS的特征良好的SOD1G93A小鼠模型。我们在阶段的交付 成为丝线激动剂（S），准备进行Sttr II期辅助研究和验证 在扩大数量的孤儿疾病中，为将来的人类试验做准备。