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: 9901962
• 负责人: Gerald W. Dorn
• 金额: $ 25.44万
• 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 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901962
• 关键词: Adolescent; Affect; Age; Agonist; Alleles; American; Amyotrophic Lateral Sclerosis; Atrophic; Binding Proteins; Biological Availability; Biotechnology; Blinded; Brain; Capital Financing; Caregivers; Caring; Cell model; Cells; Charcot-Marie-Tooth Disease; Chemicals; Child; Childhood; Controlled Study; DNA Sequence Alteration; Data; Defect; Degenerative Disorder; Diagnosis; Disease; Distal; Drug Kinetics; FDA approved; Family; Fibroblasts; Forearm; Funding; Genes; Genetic; Goals; Growth; Hand; Hand Strength; Healthcare; Histology; Hour; Human; Huntington Disease; Intramuscular; Investigation; Lead; Leg; Life; Limb structure; Metabolism; Mitochondria; Modification; Molecular Conformation; Motion; Mus; Muscular Atrophy; Muscular Dystrophies; Mutation; Natural regeneration; Nerve; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Neuropathy; Onset of illness; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Plasma; Preparation; Prevention; Probability; Proteins; Quality of life; Randomized; Rare Diseases; Resources; Safety; Small Business Technology Transfer Research; Technology; Toxic effect; Universities; Validation; Variant; Washington; Wheelchairs; arm; biomarker identification; cell motility; commercialization; disability; disease-causing mutation; drug metabolism; efficacy study; first-in-human; fitness; foot; grasp; humanized mouse; improved; in vivo; inhibitor/antagonist; medical schools; mitochondrial dysfunction; mitochondrial fitness; motility disorder; mouse model; mutant; nerve injury; nervous system disorder; neuromuscular; novel drug class; pre-clinical; prevent; programs; rare genetic disorder; repaired; research and development; response to injury; sciatic nerve; skeletal; small molecule; tissue culture; 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. Mitochondria in Motion, Inc. will develop and produce investigational first-in-class small molecule mitofusin agonists, under an FDA approved IND, to treat CMT2A and other neurological diseases. Mitofusin agonists enhance mitochondrial fitness, metabolism, and trafficking within cells, thus improving homeostatic functioning and injury-responses of neurons adversely impacted by MFN2 genetic mutations. Here, we hypothesized that activating endogenous, genetically normal MFN2 and MFN1 will reverse dominant inhibition by CMT2A MFN2 mutants of neuronal mitochondrial fusion and trafficking, thus delaying or preventing CMT2A-induced neuromuscular degeneration. Our immediate goals are to refine our lead mitofusin agonist for in vivo administration (SA#1) and to provide proof-of-concept for in vivo mitofusin agonist efficacy in a mouse model of aggressive CMT2A (SA#2) to support our preclinical data in CMT2A patient- derived cells. 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 in this 1 year Phase I STTR will be a mitofusin agonist(s) ready for STTR Phase II IND-enabling studies in CMT2A and validation in an expanded number of orphan diseases, in preparation for anticipated first-in-human trials.

丝裂霉素激动剂预防腓骨肌萎缩症 2A 杰拉尔德·多恩二世 (Gerald W Dorn II)，医学博士 线粒体运动公司 华盛顿大学圣路易斯医学院 摘要：2A 型腓骨肌萎缩症 (CMT) 是一种无法治愈的疾病，主要是 由以下原因引起的儿童常染色体显性神经肌肉退行性疾病 线粒体融合蛋白 (MFN) 2 基因突变目前尚无改变疾病的因素。 Mitochondria in Motion, Inc. 将开发和生产研究性疗法。 根据 FDA 批准的 IND，一流的小分子线粒体融合蛋白激动剂 Mitofusin 激动剂可增强治疗 CMT2A 和其他神经系统疾病的作用。 线粒体健康、新陈代谢和细胞内运输，从而改善 神经元的稳态功能和损伤反应受到不利影响 在这里，我们开发了激活内源性的 MFN2 基因突变。 遗传正常的 MFN2 和 MFN1 将逆转 CMT2A 的显性抑制 神经元线粒体融合和运输的 MFN2 突变体，从而延迟或 预防 CMT2A 引起的神经肌肉变性是我们的近期目标。 我们的目标是改进我们用于体内给药的主要线粒体融合蛋白激动剂 (SA#1) 并 为小鼠模型中线粒体融合蛋白激动剂的体内功效提供概念验证 积极的 CMT2A (SA#2) 来支持我们在 CMT2A 患者中的临床前数据- 我们将满足未满足的医疗保健需求并建立商业细胞。 企业通过 CMT2A 为约 10,000 名美国人提供服务，并为超过 200,000 名美国人提供服务 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、肌萎缩侧索硬化症、 我们在这一 1 年期 STTR 中的成果将是 线粒体融合蛋白激动剂已准备好进行 STTR II 期 CMT2A 和 IND 启用研究 在更多的孤儿疾病中进行验证，为 预期首次人体试验。