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：一些罕见的神经退行性疾病的特点是， 线粒体断裂、运动障碍和功能障碍。其中包括肌萎缩性 脊髓侧索硬化症（ALS）和亨廷顿病（HD），其引起显著的 受影响人口的发病率和死亡率， 改变疾病的疗法在第一阶段STTR的支持下，Mitochondria in Motion，Inc. (MiM)已经开发出第一种药学上可接受的小分子丝裂融合素 活化剂来治疗这些和其他神经退行性病症， 线粒体病理线粒体融合蛋白激活增强线粒体 健康，代谢和贩运内患病的神经元，从而改善 稳态功能，赋予对损伤的抵抗力并促进神经元 修复/再生。在第一阶段，我们假设用丝裂融合素 激活剂将对病因多样的遗传外周 线粒体神经病变第一阶段证实了这一概念 MiM正在推进2种临床前领先的丝裂融合蛋白激活剂，CPR 1-B， 在遗传异质性疾病（如ALS和HD）中持续激活， 通过线粒体融合蛋白（MFN）突变，和MiM-111在Charcot-Marie中的“爆发”激活， 2A型牙病（CMT 2A）是由MFN 2突变直接引起的。具有 将CPR 1-B确定为ALS和HD等非CMT 2A神经病的临床候选药物， 我们的第二阶段目标是启动非GMP的IND前研究，使我们能够获得FDA IND 批准（目标1），并定义ALS和HD中的最佳CPR 1-B给药水平和时间表 小鼠模型（Aim 2）。如果成功，我们将填补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ALS患者和约150，000名 患有HD或有遗传风险的美国人，他们的照顾者和 家庭我们在第二阶段的交付成果将是一种定位于FDA IND的米托霉素激活剂 批准和第一阶段首次人体试验。

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: A number of rare neurodegenerative diseases are characterized by mitochondrial fragmentation, dysmotility and dysfunction. Among these are Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease (HD), which cause significant morbidity and mortality in affected populations and for which there are no available disease-altering therapies. With Phase I STTR support, Mitochondria in Motion, Inc. (MiM) has developed the first pharmaceutically acceptable small molecule mitofusin activators to treat these and other neurodegenerative conditions with underlying contributory mitochondrial pathology. Mitofusin activation enhances mitochondrial fitness, metabolism and trafficking within diseased neurons, thereby improving homeostatic functioning, conferring resistance to injury and promoting neuronal repair/regrowth. During phase I we hypothesized that intervention with a mitofusin activator would have beneficial effects on etiologically diverse genetic peripheral neuropathies with a mitochondrial component. This notion was validated by phase I studies and MiM is advancing 2 pre-clinical lead mitofusin activators, CPR1-B for sustained activation in genetically heterogenous diseases like ALS and HD not caused by mitofusin (MFN) mutations, and MiM-111 for “burst” activation in Charcot-Marie- Tooth disease type 2A (CMT2A) that is directly caused by mutations in MFN2. Having identified CPR1-B as a clinical candidate in non-CMT2A neuropathies like ALS and HD, our Phase II goals are to initiate non GMP pre-IND studies positioning us for FDA IND approval (Aim 1) and define optimal CPR1-B dosing levels and schedule in ALS and HD mouse models (Aim 2). If successful 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. Our deliverable in Phase II will be a mitofusin activator positioned for FDA IND approval and phase 1 first-in-human trials.