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 翻译后摘要：有一些罕见的神经退行性疾病，包括 肌萎缩性侧索硬化症（ALS）和亨廷顿病（HD）， 没有可用或有效的治疗，并导致显著的发病率和死亡率， 受影响的人口。运动中的线粒体将开发和生产 在FDA批准的一项研究中， 来治疗这些疾病。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， 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 已发表的线粒体融合素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点Mitofusin 2突变引起。这里我们 假设用丝裂融合素激动剂进行干预会对 其他具有线粒体成分的遗传性周围神经病， 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20000 患有ALS的美国人和约150，000名患有或有遗传风险的美国人 发展中的HD，他们的照顾者和家庭。在第一阶段STTR中，我们建议 优化用于全身给药的丝裂霉素激动剂的药代动力学性质 给药和血脑屏障渗透（目的1），并在体内完成 丝裂融合素激动剂延缓糖尿病患者疾病进展的可行性和验证研究 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 作为一种丝裂霉素激动剂，准备进行STTR II期IND使能研究和验证 更多孤儿疾病的研究，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.