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: 10521289
• 负责人: Elena N. Dedkova
• 金额: $ 39.25万
• 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/10521289
• 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，没有FDA批准 疗法FA的病理生理机制是由一种线粒体蛋白，共济失调蛋白（FXN）， 在铁硫（Fe-S）簇生物成因中起作用。症状通常在5至15岁之间开始， 随着时间的推移而恶化。尽管感觉和平衡缺陷使FA患者坐在轮椅上，但几乎所有FA患者都死于 心肌病目前，还没有改善FA心肌病的药物疗法，大多数FA患者死于心脏病。 30多岁的心肌病患者 我们确定了FA人成纤维细胞的氧化还原缺陷，并利用它筛选了1600种药物的库， 安全地用于人类，以测试它们防止FA中细胞死亡的能力。我们确定了富马酸二甲酯（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）和银屑病的药物。最 在FA的生理小鼠模型（FXNKD）中，我们发现1）DMF剂量依赖性地拯救FXN水平， 心肌线粒体Fe-S簇酶乌头酸酶和琥珀酸脱氢酶活性; 2）DMF显著降低心肌线粒体Fe-S簇酶活性 在小鼠中挽救了类似于人FA心脏缺陷的三种严重心脏缺陷：a）左心室肥大; B） 每搏输出量减少;和c）心输出量减少。初步数据支持DMF正在提供 线粒体->共济蛋白-> Fe-S簇通过Nrf 2依赖性机制支持。 此外，我们最近合成了一种称为IMF的替代MMF前药，具有改善的药代动力学 可能比DMF更有效。因此，我们假设，DMF/IMF的替代物代表了一种新的 治疗策略，可以潜在地重新用于致命的心肌病在FA。目前工作的目的 旨在确定DMF/IMF对FA中最受影响组织（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的安全、毒理和DMPK 因此，它可以比必须通过广泛的临床试验的新化合物更快地进入临床试验。 安全性和毒理学测试，然后才能用于临床试验。然而，在尝试使用药物之前， FA患者，完成DMF/IMF的“临床前包装”及其对心脏/骨骼肌的作用 FA中的保护是重要的，可以在三个具体目标中解决。目标1旨在确定最佳 DMF和IMF的剂量，挽救心脏和骨骼肌缺陷。目标2旨在确定机制 负责FXNKD小鼠的功能恢复。目的3旨在确定是否最佳剂量的 DMF/IMF延长具有心脏特异性FXN KO（MCK-Cre）的小鼠的寿命。这些目标累积起来将 生成DMF和IMF用于FA致死性心肌病的潜在临床前数据。因为DMF是 已经批准用于人类，安全性/DMPK/毒理学和I期研究已经完成，它具有更大的 有机会“快速跟踪”治疗FA中的心肌病。