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

预防夏科-玛丽-图斯病的丝裂霉素激动剂 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：2A型Charcot-Marie-Tooth(CMT)病是一种不治之症，主要 儿童常染色体显性遗传性神经肌肉退行性疾病由 丝裂原蛋白(MFN)2基因突变。目前还没有改变疾病的方法 治疗。有了第一阶段STTR支持，运动中的线粒体公司 开发出首个药物可接受的小分子丝裂原丝裂原 用于治疗CMT2A和可能的其他神经系统疾病的激活剂。总体而言, 丝裂原激活增强线粒体的适合性、新陈代谢和运输 在神经元内，从而改善内稳态功能和损伤反应。 我们的临床领先的丝裂原激活剂Trans-MiM111使线粒体正常化 CMT2A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CMT2A的小鼠的神经肌肉功能障碍 Mfn2体内突变体(T105M)。在STTR第一阶段，我们验证了我们的 激活内源性、遗传正常的Mfn2和Mfn1的假说 能逆转CMT2AMfn2突变体对神经细胞的显性抑制 线粒体融合和运输，从而防止CMT2A诱导 神经肌肉变性。在确定了一种在药物上可以接受的 临床候选药物TRANS-MiM111，我们的第二阶段目标是定义最佳剂量 使用我们的CMT2A鼠标(SA#1)的级别和时间表，并启动GLP(非 GMP)进行IND前研究，以使我们获得FDA批准的首例人体试验。如果 我们是成功的，我们将满足未得到满足的医疗需求，并建立一个商业 企业将通过CMT2A和&gt；20万为大约10,000名美国人提供服务 患有其他神经退行性疾病的美国人的特征是 线粒体变性，包括CMT 1型，肌萎缩侧索硬化症， 和亨廷顿氏症。我们这项为期2年的第二阶段STR的交付内容将是 Mitofusin激活剂定位于FDA批准和第一阶段，首次用于人体试验。

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.