Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A

预防腓骨肌萎缩症的线粒体融合素激动剂2A 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：腓骨肌萎缩症（CMT）疾病2A型是一种不治之症，主要是 儿科常染色体显性遗传神经肌肉退行性疾病，由 Mitofusin（MFN）2基因突变。目前还没有改变疾病的 治疗。在第一阶段STTR的支持下，Mitochondria in Motion，Inc.具有 开发了第一个药学上可接受的小分子丝裂霉素 激活剂治疗CMT 2A和可能的其他神经系统疾病。总的来说， 丝裂融合蛋白激活增强线粒体适应性、代谢和运输 在神经元内，从而改善稳态功能和损伤反应。 我们的临床领先的线粒体融合蛋白激活剂trans-MiM 111， CMT 2A患者成纤维细胞和体外重编程神经元的异常， 并逆转表达人CMT 2A的小鼠的神经肌肉功能障碍 MFN 2突变体（T105 M）体内。在STTR第一阶段，我们验证了 激活内源性、遗传正常的MFN 2和MFN 1的假说 可以逆转CMT 2A MFN 2突变体对神经元的显性抑制， 线粒体融合和运输，从而阻止CMT 2A诱导的 神经肌肉变性在确定了一种药学上可接受的 临床候选药物trans-MiM 111，我们的II期目标是确定最佳剂量 使用我们的CMT 2A小鼠（SA#1）的水平和时间表，并启动GLP（非 GMP）pre-IND研究，使我们能够获得FDA批准的首次人体试验。如果 如果我们成功了，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10，000名美国人提供CMT 2A服务， 患有其他神经退行性疾病的美国人， 线粒体变性，包括CMT 1型，肌萎缩侧索硬化， 和亨廷顿舞蹈症。我们为这2年第二阶段STTR交付的成果将是 丝裂融合素激活剂定位为FDA批准和I期，首先在人类，试验。

Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: Charcot-Marie-Tooth (CMT) disease type 2A is an incurable, primarily pediatric, autosomal dominant neuromuscular degenerative disease caused by mutations in the mitofusin (MFN) 2 gene. There are currently no disease-altering treatments. With Phase I STTR support, Mitochondria in Motion, Inc. has developed the first pharmaceutically acceptable small molecule mitofusin activator to treat CMT2A and possibly other neurological diseases. In general, mitofusin activation enhances mitochondrial fitness, metabolism, and trafficking within neurons, thus improving homeostatic functioning and injury-responses. Our clinical lead mitofusin activator, trans-MiM111, normalizes mitochondrial abnormalities in CMT2A patient fibroblasts and reprogrammed neurons in vitro, and reverses neuromuscular dysfunction in mice expressing a human CMT2A MFN2 mutant (T105M) in vivo. During STTR Phase I we validated our hypothesis that activating endogenous, genetically normal MFN2 and MFN1 could reverse dominant inhibition by CMT2A MFN2 mutants of neuronal mitochondrial fusion and trafficking, thus preventing CMT2A-induced neuromuscular degeneration. Having identified a pharmaceutically acceptable clinical candidate, trans-MiM111, our Phase II goals are to define optimal dosing levels and schedule using our CMT2A mouse (SA#1), and initiate GLP (non- GMP) pre-IND studies to position us for FDA approval of first-in-human trials. If we are successful, we will fill an unmet healthcare need and build a commercial enterprise to serve the ~10,000 Americans with CMT2A and the >200,000 Americans suffering from other neurodegenerative diseases characterized by mitochondrial degeneration, including CMT type 1, amyotrophic lateral sclerosis, and Huntington’s disease. Our deliverable for this 2 year Phase II STTR will be a mitofusin activator positioned for FDA approval and phase I, first in human, trials.