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.

治疗神经退行性疾病的丝裂原激动剂 Gerald W Dorn II，医学博士 运动中的线粒体公司 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(ALS)和亨廷顿病(HD)，有 没有可用的或有效的治疗方法，导致严重的发病率和死亡率 受影响的人口。运动中的线粒体公司将开发和生产 FDA批准的研究中的一流小分子丝裂原激动剂 IND，来治疗这些疾病。Mitofusin激动剂增强线粒体适合性， 新陈代谢和细胞内转运，从而改善体内平衡功能和 受遗传线粒体功能障碍影响的细胞的损伤反应。我们的 已发表的丝裂原激动剂的疾病焦点是Charcot-Marie-Tooth病型 2A，由我们药物的蛋白质靶标Mitofusin 2突变引起。在这里，我们 假设用丝裂原激动剂干预会对 其他带有线粒体成分的遗传性周围神经病，这是 由我们在ALS和HD患者来源的细胞中的临床前数据支持。因此，我们将填补 未得到满足的医疗保健需求，并建立一家商业企业，为约20,000人提供服务 患有肌萎缩侧索硬化症的美国人和大约15万患有或面临遗传风险的美国人 发展HD，他们的照顾者和家庭。在本阶段中，我们建议 全身性丝裂原丝裂原激动剂药代动力学性质的优化 给药和血脑屏障穿透(目标1)，并在体内完成 丝裂原丝裂原激动剂延缓疾病进展的可行性和有效性研究 ALS的SOD1G93A小鼠模型。我们在第一阶段的交付成果将 作为丝裂原激动剂(S)为STTRII期IND使能研究和验证做好准备 在越来越多的孤儿疾病中，为未来的第一次人体试验做准备。