MITOFUSIN AGONISTS TO TREAT NEURODEGENERATIVE DISEASE

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 硬化症(ALS)和亨廷顿病(HD)，目前还没有可用的或有效的治疗方法 并在受影响人群中导致显著的发病率和死亡率。运动中的线粒体 Inc.将开发和生产研究一流的小分子丝裂原激动剂，根据 FDA批准了IND，用于治疗这些疾病。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损伤反应 受到遗传线粒体功能障碍不利影响的细胞。我们出版的疾病焦点是 Mitofusin激动剂是由我们药物的突变引起的2A型Charcot-Marie-Tooth病 蛋白质靶标，Mitofusin 2。在这里，我们假设用丝裂原激动剂进行干预将 对其他具有线粒体成分的遗传性周围神经病有有益影响， 这得到了我们在ALS和HD患者来源细胞中的临床前数据的支持。因此，我们将填补 一个未得到满足的医疗保健需求，并建立一个商业企业，为大约20,000名美国人提供服务 肌萎缩侧索硬化症和大约150,000名患有HD或有遗传风险的美国人，他们的照顾者 和家人。在这个第一阶段，我们建议优化药物的药代动力学特性。 用于全身给药和血脑屏障穿透的丝裂霉素激动剂(目标1)，以及 完成丝裂原激动剂延缓疾病进展的体内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是 丝裂霉素激动剂(S)准备用于STTR第二阶段IND-使能研究和验证在扩大的 孤儿疾病的数量，为未来的第一次人体试验做准备。

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.