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

丝裂霉素激动剂预防腓骨肌萎缩症 2A

• 批准号: 10471364
• 负责人: Gerald W. Dorn
• 金额: $ 90.18万
• 依托单位: MITOCHONDRIA IN MOTION, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471364
• 关键词: 20 year old; Address; Agonist; American; Amyotrophic Lateral Sclerosis; Biological Assay; Biotechnology; Canis familiaris; Cells; Charcot-Marie-Tooth Disease; Chemicals; Child; Childhood; Clinic; Clinical; Clinical Trials; Degenerative Disorder; Development; Diabetic Neuropathies; Disease; Dose; Drug Targeting; Fibroblasts; Follow-Up Studies; Forearm; Formulation; Functional disorder; Funding; Genes; Genetic; Geography; Goals; Government; Grant; Hand; Health; Healthcare; Hour; Human; Huntington Disease; Impairment; In Vitro; Interruption; Lead; Leg; Life; Lower Extremity; Metabolism; Mitochondria; Modeling; Morphology; Motion; Motor; Motor Neurons; Mus; Muscular Atrophy; Muscular Dystrophies; Mutation; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Oral; Oral Administration; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Proteins; Publishing; Rare Diseases; Rattus; Research; Resources; Safety; Schedule; Sensory; Small Business Technology Transfer Research; Therapeutic; Therapeutic Index; Toxic effect; Translating; Universities; Upper Extremity; Washington; Wheelchairs; cell motility; chemotherapy; clinical candidate; commercialization; disability; disease diagnosis; disease-causing mutation; efficacy evaluation; first-in-human; foot; improved; in vivo; medical schools; mitochondrial fitness; mutant; nervous system disorder; neuromuscular; non-genetic; novel strategies; patient advocacy group; pharmacokinetics and pharmacodynamics; physical state; pre-clinical; prevent; programs; research and development; response to injury; sciatic nerve; screening; small molecule; therapeutically effective; trafficking; young adult

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.

丝线激动剂预防charcot-marie-tooth病2a Gerald W Dorn II，医学博士 线粒体运动公司 圣路易斯医学院华盛顿大学 摘要：Charcot-Marie-Tooth（CMT）2A型疾病是无法治愈的主要原理 小儿，常染色体显性神经肌肉退行性疾病由 丝线（MFN）2基因中的突变。目前没有改变疾病的 治疗。借助I期STTR支持，Mitochondia In Motion，Inc。具有 开发了第一个物理上可接受的小分子丝线反蛋白 激活剂治疗CMT2A和可能的其他神经系统疾病。一般来说， 线粒体激活增强了线粒体适应性，代谢和贩运 在神经元内，从而改善了稳态功能和损伤反应。 我们的临床铅丝线激活剂Trans-MIM111使丝线素激活剂归一化 CMT2A患者成纤维细胞和重编程神经元的异常，体外， 并逆转表达人CMT2A的小鼠的神经肌肉功能障碍 MFN2突变体（T105M）在体内。在STTR阶段，我们验证了我们的 假设激活内源性，通常正常的MFN2和MFN1 CMT2A MFN2突变体的神经元可能会逆转抑制作用 线粒体融合和运输，从而防止CMT2A诱导 神经肌肉变性。已经确定了身体上可以接受的 临床候选者Trans-MIM111，我们的II期目标是定义最佳剂量 使用我们的CMT2A鼠标（SA＃1）进行级别和安排，并启动GLP（非 - GMP）预先研究将我们定位为FDA批准的人类试验。如果 我们成功，我们将满足未满足的医疗保健需求并建立广告 企业为约有10,000名美国人提供CMT2A和> 200,000的美国人 患有其他神经退行性疾病的美国人，其特征是 线粒体变性，包括1型CMT，肌萎缩性侧硬化症， 和亨廷顿氏病。我们在这2年第二阶段STTR的交付将是一个 丝线激活剂定位用于FDA批准和I期，首先是人类试验。