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.

Friedreich的共济失调（FA）是最常见的遗传性共济失调，没有FDA批准 治疗。 FA的病理生理机制是由仅减少一种线粒体蛋白（FXN）， 这在铁硫（FE-S）簇生物发生中起作用。症状通常从5到15岁的年龄开始， 随着时间的流逝恶化。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，没有药物疗法可以改善FA心肌病，而大多数FA死亡 他们30多岁的心肌病。 我们确定了FA人类成纤维细胞中的氧化还原缺乏症，并用它来筛选1600种药物的库 安全地用于人类，以测试其防止FA细胞死亡的能力。我们鉴定了富马酸二甲基（DMF），A 单甲基富马酸酯（MMF）的前驱前体是所有测试药物中最保护的。 DMF（也称为 Tecfidera和Skilarence）是FDA批准的多发性硬化症（MS）和牛皮癣的药物。最多 FA的生理小鼠模型（FXNKD），我们发现1）DMF剂量依赖性地营救了FXN水平和 线粒体Fe-s簇酶刺激酶和心脏中的琥珀酸酯脱氢酶活性； 2）DMF显着 挽救了类似于人FA心脏缺陷的小鼠中的三个关键心脏缺陷：a）左心室肥大； b） 中风量减少； c）心脏输出降低。初步数据支持DMF提供的主张 线粒体 - > frataxin-> Fe-S簇通过NRF2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，并具有改进的药代动力学 这可能比DMF更有效。因此，我们假设烟熏DMF/IMF代表了一种小说 可以重新使用FA致死性心肌病的治疗策略。当前工作的目的 是为了确定DMF/IMF对FA（心脏和骨骼肌）中大多数受影响组织的功能，以及 确定保护作用的机制。 DMF已经通过FDA的安全，毒理学和DMPK 障碍，因此可能要比必须经过广泛的新化合物更快地进入临床试验 安全性和毒理学测试可以在临床试验中使用。但是，在尝试使用该药物之前 具有FA的人，DMF/IMF的“临床前套件”及其在心脏/骨骼肌肉中的作用 FA的保护很重要，可以在三个特定目标中解决。 AIM 1旨在确定最佳 DMF和IMF的剂量挽救心脏和骨骼肌缺陷。 AIM 2旨在确定机制 负责FXNKD鼠标中的功能恢复。 AIM 3旨在确定是否最佳剂量 DMF/IMF使用心脏特异性FXN KO（MCK-CRE）延长小鼠的寿命。累计这些目标将 生成临床前数据，用于在FA中使用DMF和IMF用于致命性心肌病。因为DMF是 已经批准用于安全/DMPK/毒理学和I期研究已经完成的人类使用，它具有更大的 在FA中，有机会“快速入路”以治疗心脏肌病。