MITOFUSIN AGONISTS TO TREAT NEURODEGENERATIVE DISEASE

用于治疗神经变性疾病的线粒体融合素激动剂 Gerald W多恩二世，医学博士 运动中的线粒体 华盛顿大学圣刘易斯医学院 摘要：有一些罕见的神经退行性疾病，包括肌萎缩侧索硬化症， 硬化症（ALS）和亨廷顿氏病（HD），对于这些疾病没有可用或有效的治疗 并导致受影响人口的发病率和死亡率很高。运动中的线粒体 Inc.将开发和生产研究一流的小分子丝裂融合素激动剂，根据 FDA批准的IND，用于治疗这些疾病。线粒体融合素激动剂增强线粒体适应性， 代谢和细胞内的运输，从而改善稳态功能和损伤反应 受到遗传线粒体功能障碍不利影响的细胞。我们发表的疾病焦点， 线粒体融合素激动剂是Charcot-Marie-Tooth病2A型，由我们的药物突变引起。 蛋白质靶标，线粒体融合蛋白2。在这里，我们假设用丝裂融合素激动剂干预， 对其他具有线粒体成分的遗传性周围神经病具有有益的作用， 这得到了我们在ALS和HD患者来源的细胞中的临床前数据的支持。我们将填补 一个未满足的医疗保健需求，并建立一个商业企业，为约20,000名美国人提供服务， ALS和约150，000名患有HD或有遗传风险的美国人，他们的照顾者 和家人在本I期STTR中，我们建议优化以下药物的药代动力学性质： 用于全身给药和血脑屏障穿透的丝裂霉素激动剂（Aim 1），和 完成线粒体融合素激动剂延迟疾病进展的体内可行性和验证研究， 已充分表征的SOD 1G 93 A ALS小鼠模型。我们在第一阶段的成果将是 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 孤儿疾病的数量，为未来的首次人体试验做准备。

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.