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：许多罕见的神经退行性疾病的特点是 线粒体碎裂、运动障碍和功能障碍。其中包括肌营养 侧索硬化症(ALS)和亨廷顿病(HD)，这两种疾病会导致显著的 受影响人群的发病率和死亡率，目前尚无相关数据 改变疾病的疗法。在第一阶段STTR支持下，运动中的线粒体公司。 (MIM)开发出第一个在药物上可接受的小分子丝裂原丝裂原 激活剂治疗这些和其他神经退行性疾病 导致线粒体病理改变。丝裂原激活增强线粒体 适合性、新陈代谢和疾病神经元内的运输，从而改善 动态平衡功能，赋予损伤抵抗和促进神经元 修复/再生。在第一阶段，我们假设使用有丝分裂素进行干预 激活剂将对病因性不同的遗传外周有有益的影响 带有线粒体成分的神经病。这一概念在第一阶段得到了验证。 研究和MIM正在开发2种临床前丝裂原激活剂，CPR1-B用于 ALS和HD等遗传异质性疾病的持续激活不是原因 通过丝裂素(MFN)突变和MIM-111在Charcot-Marie- 由Mfn2基因突变直接引起的2A型牙病(CMT2A型)。拥有 确定CPR1-B是ALS和HD等非CMT2A型神经疾病的临床候选基因， 我们的第二阶段目标是启动非GMP Pre-IND研究，为FDA Ind定位 批准(目标1)并确定ALS和HD的最佳CPR1-B剂量水平和计划 小鼠模型(目标2)。如果成功，我们将满足未得到满足的医疗需求，并建立 为约20,000名患有肌萎缩侧索硬化症的美国人和约150,000名美国人服务的商业企业 患有HD或有患HD基因风险的美国人，他们的照顾者和 家人。我们在第二阶段交付的产品将是为FDA Ind定位的丝裂原激活剂 批准和第一阶段首例人体试验。

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.