Fumarate drugs rescue cardiac dysfunction in mouse models of Friedreich's ataxia

富马酸盐药物可挽救弗里德赖希共济失调小鼠模型的心功能障碍

• 批准号: 10730316
• 负责人: Elena N. Dedkova
• 金额: $ 7.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10730316
• 关键词: Aconitate Hydratase; Address; Affect; Age; Animals; Ataxia; Biochemical; Biogenesis; Biological Assay; Body Weight decreased; Cardiac; Cardiac Output; Cardiomyopathies; Cell Death; Cessation of life; Clinical Trials; Complex; Data; Defect; Development; Dose; Drug Kinetics; Drug usage; Enzymes; Equilibrium; FDA approved; Fibroblasts; Fibrosis; Freezing; Friedreich Ataxia; Fumarates; Gender; Hand Strength; Heart; Heart Abnormalities; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histopathology; Human; Impairment; Inherited; Iron; Knockout Mice; Left Ventricular Ejection Fraction; Left Ventricular Hypertrophy; Libraries; Longevity; Mediating; Mitochondria; Mitochondrial Proteins; Multiple Sclerosis; Mus; Muscle; Muscle Mitochondria; Muscle function; Myocardial dysfunction; Myocardium; Myopathy; Necrosis; Neurologic Deficit; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Prodrugs; Proteomics; Psoriasis; Recovery of Function; Role; Rotarod Performance Test; Safety; Sampling; Sensory; Signal Pathway; Skeletal Muscle; Stroke Volume; Succinate Dehydrogenase; Sulfur; Survival Analysis; Symptoms; Testing; Thick; Time; Tissues; Toxicology; Two-Dimensional Echocardiography; Weight; Wheelchairs; Work; cardioprotection; design; drug testing; efficacy testing; enzyme activity; frataxin; heart function; improved; in vivo; knock-down; mortality; mouse model; multiple sclerosis treatment; mutant; novel therapeutic intervention; phase 1 study; pre-clinical; prevent; response; sex

Friedreich's Ataxia (FA) is the most common inherited recessive ataxia, for which there is no FDA-approved therapy. FA's pathophysiological mechanism is caused by the reduction of just one mitochondrial protein, frataxin (FXN), that functions in iron-sulfur (Fe-S) cluster biogenesis. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. Although sensory and balance deficits put FA patients in wheelchairs, nearly all FA patients die of cardiomyopathy. Currently, there are no drug therapies that ameliorate FA cardiomyopathy and most with FA die of the cardiomyopathy in their 30s. We identified redox deficiency in FA human fibroblasts, and used this to screen a library of 1600 drugs already safely used in humans, to test for their ability to prevent cell death in FA. We identified dimethyl fumarate (DMF), a prodrug precursor of monomethyl fumarate (MMF), as the most protective among all tested drugs. DMF (also known as Tecfidera and Skilarence) is the FDA approved drug for treatment of multiple sclerosis (MS) and psoriasis. In the most physiological mouse model of FA (the FXNKD), we found that 1) DMF dose-dependently rescued FXN levels and the mitochondrial Fe-S cluster enzymes aconitase and succinate dehydrogenase activity in the heart; 2) DMF significantly rescued three critical cardiac deficits in mice that resemble human FA cardiac defects: a) left ventricular hypertrophy; b) decreased stroke volume; and c) decreased cardiac output. Preliminary data support the claim that DMF is providing mitochondrial->frataxin-> Fe-S cluster support via Nrf2-dependent mechanism. Additionally, we recently synthesized an alternative MMF prodrug called IMF, with improved pharmacokinetics that may be even more potent than DMF. Therefore, we hypothesize that fumarates DMF/IMF represent a novel therapeutic strategy that can potentially be repurposed for the lethal cardiomyopathy in FA. The aim of the current work is to determine the effects of DMF/IMF on the function of most affected tissues in FA (heart and skeletal muscles), and to determine the mechanism of protective action. DMF has already passed through FDA's safety, toxicology and DMPK hurdles, and thus could enter clinical trials much more quickly than a new compound that must pass through extensive safety and toxicology testing before it could be used in clinical trials. However, before attempting to use the drug in humans with FA, completion of the 'pre-clinical package' for DMF/IMF and their role for cardiac/skeletal muscle protection in FA are important, and can be addressed in the three Specific Aims. Aim 1 is designed to determine optimal dosing of DMF & IMF that rescue cardiac and skeletal muscles deficits. Aim 2 is designed to determine the mechanism responsible for functional recovery in the FXNKD mouse. Aim 3 is designed to determine whether optimal dosing of DMF/IMF extends the life span of mouse with cardiac-specific FXN KO (MCK-Cre). Cumulatively these aims will generate pre-clinical data for the potential use of DMF and IMF for lethal cardiomyopathy in FA. Because DMF is already approved for use in humans with safety/DMPK/toxicology and Phase I studies already completed, it has a greater opportunity to be 'fast-tracked' for treatment of cardiac myopathy in FA.

弗里德赖希共济失调 (FA) 是最常见的遗传性隐性共济失调，目前尚无 FDA 批准的治疗方法 治疗。 FA 的病理生理机制是由一种线粒体蛋白 frataxin (FXN) 的减少引起的， 在铁硫（Fe-S）簇生物发生中发挥作用。症状通常在 5 至 15 岁之间开始，并且 随着时间的推移恶化。尽管感觉和平衡缺陷使 FA 患者不得不坐在轮椅上，但几乎所有 FA 患者均死于 心肌病。目前，尚无改善 FA 心肌病的药物疗法，大多数 FA 患者死于 30多岁得心肌病。 我们发现了 FA 人成纤维细胞中的氧化还原缺陷，并利用它筛选了包含 1600 种药物的库 安全地用于人类，以测试其预防 FA 细胞死亡的能力。我们鉴定出富马酸二甲酯 (DMF) 富马酸单甲酯（MMF）的前药前体，是所有测试药物中最具保护性的。 DMF（也称为 Tecfidera 和 Skilarence）是 FDA 批准的用于治疗多发性硬化症 (MS) 和牛皮癣的药物。在最 在 FA (FXNKD) 生理小鼠模型中，我们发现 1) DMF 剂量依赖性地挽救了 FXN 水平，并且 心脏中线粒体 Fe-S 簇酶乌头酸酶和琥珀酸脱氢酶活性； 2）DMF显着 挽救了小鼠的三种严重心脏缺陷，类似于人类 FA 心脏缺陷：a) 左心室肥大； b) 每搏输出量减少； c) 心输出量减少。初步数据支持 DMF 提供的主张 通过 Nrf2 依赖机制支持线粒体 -> frataxin -> Fe-S 簇。 此外，我们最近合成了一种名为 IMF 的替代 MMF 前药，具有改进的药代动力学 这可能比 DMF 更有效。因此，我们假设富马酸盐 DMF/IMF 代表了一种新颖的 可能重新用于 FA 致命性心肌病的治疗策略。当前工作的目的 目的是确定 DMF/IMF 对 FA 中受影响最大的组织（心脏和骨骼肌）功能的影响，并 确定保护作用的机制。 DMF已通过FDA安全、毒理学和DMPK 障碍，因此可以比必须通过广泛的新化合物更快地进入临床试验 在用于临床试验之前进行安全性和毒理学测试。然而，在尝试使用该药物之前 患有 FA 的人类，完成 DMF/IMF 的“临床前包”及其对心脏/骨骼肌的作用 FA 中的保护很重要，可以通过三个具体目标来解决。目标 1 旨在确定最佳 DMF 和 IMF 的剂量可挽救心肌和骨骼肌缺陷。目标2旨在确定机制 负责 FXNKD 小鼠的功能恢复。目标 3 旨在确定是否最佳剂量 DMF/IMF 可延长心脏特异性 FXN KO (MCK-Cre) 小鼠的寿命。累积起来，这些目标将 生成 DMF 和 IMF 治疗 FA 致死性心肌病潜在用途的临床前数据。因为 DMF 是 已批准用于人体，安全性/DMPK/毒理学且 I 期研究已完成，它具有更大的 在 FA 中“快速”治疗心肌病的机会。