Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

醛固酮抑制在杜氏肌营养不良症中的治疗潜力

基本信息

批准号：
8851666
负责人：
Jill A Rafael-Fortney
金额：
$ 70.87万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-13 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851666
关键词：
Address Adrenergic beta-Antagonists Adult Advocate Affect Aftercare Aldosterone Aldosterone Antagonists Angiotensin-Converting Enzyme Inhibitors Animal Model Attenuated Biological Markers Biological Preservation Blood Circulation Cardiac Cardiomyopathies Caring Cause of Death Cessation of life Child Clinical Clinical Research Clinical Trials Collaborations Collagen Data Deterioration Disease Disease Progression Drug Combinations Duchenne muscular dystrophy EFRAC Early treatment Echocardiography Enzyme Inhibition Family Fibrosis Functional disorder Future Gene Expression Glucocorticoid Receptor Guidelines Health Heart Heart Diseases Heart failure Histology Image Injury Left Left Ventricular Ejection Fraction Life Limb structure Lung Magnetic Resonance Masks Measurement Mediating Mineralocorticoids Molecular Models Mus Muscle Muscle Weakness Muscle function Muscular Dystrophies Myocardial Myocardium Myopathy Nuclear Receptors Outcome Pathway interactions Patients Peptidyl-Dipeptidase A Pharmaceutical Preparations Phenotype Placebos Population Preclinical Testing Provider Publications Publishing Randomized Reporting Research Design Respiratory Diaphragm Serological Serum Skeletal Muscle Spironolactone Striated Muscles Symptoms Testing Therapeutic Therapeutic Effect Translations Treatment Efficacy Type I Procollagen Ventricular Vital capacity Work boys coronary fibrosis design disability eplerenone falls improved improved functioning insight molecular modeling mortality mouse model multidisciplinary muscle degeneration muscular dystrophy mouse model muscular structure pre-clinical preclinical study randomized trial research study screening success sudden cardiac death therapeutic gene translational medicine treatment trial

项目摘要

DESCRIPTION (provided by applicant): Progress in treating pulmonary and other complications of striated muscle deterioration in Duchenne muscular dystrophy (DMD) patients has made cardiomyopathy a leading cause of mortality. Limited ambulation due to skeletal muscle weakness in DMD often masks typical symptoms seen in other populations with myocardial disease, allowing unchecked disease progression. Without aggressive screening, DMD patients' first manifestation of heart disease may be severe heart failure or sudden cardiac death. Our group and others have detected myocardial fibrosis in DMD patients prior to reduction in left ventricular ejection fraction (EF) using cardiac magnetic resonance (CMR). Also, with CMR-derived strain measurement, a more sensitive marker of contractile dysfunction, we have found subclinical decline that occurs annually. Recognizing fibrosis with preserved EF led to the idea that old cardiac drugs with reported 'antifibrotic' effect might be beneficial in DD cardiomyopathy. An engaged family launched a fundraising effort that fueled rapid testing of our hypothesis. We subsequently published in less than 12 months from start date remarkable preclinical data showing that early treatment of a DMD mouse model with aldosterone inhibition plus an angiotensin converting enzyme inhibitor (ACEI) affords dramatic reduction in muscle injury and preserved muscle function in both heart and skeletal muscles. Current guidelines advocate initiation of e.g. an angiotensin converting enzyme inhibitor (ACEI) when the EF falls below normal, but our data suggest that earlier treatment should be considerably more beneficial. We have made significant progress since publication of this work in August 2011 that will allow us to rapidly execute 3 essential next steps: i) a preclinical study designed to identif the optimal aldosterone antagonist for the dystrophic heart; ii) a cardiac clinical trial with structural, functional and serological endpoints; and iii) a mechanistic study focused on defining pathways of efficacy in order to optimize future treatment of all affected muscles in DMD. To address these critical issues, we have assembled a strong interdisciplinary team to execute both a landmark patient study of aldosterone antagonism plus ACEI in preserved EF DMD boys and parallel mouse experiments to precisely define which nuclear receptors in different striated muscle types mediate the observed therapeutic effects. In proving our hypotheses regarding efficacy in attenuating preclinical changes, the clinical studies will use state-of-the-art noninvasive CMR biomarkers of subclinical contractile dysfunction and fibrosis. This data will provide much-needed evidence for patients, families and providers dealing with this devastating disease that existing drugs - already in use for other indications in children and adults - offer a potential cardioprotective benefit. Successful execution of the preclinical studies will provide th necessary insights for rational design of therapeutics to have the greatest impact on reducing death and disability in patients with DMD.

描述（由申请人提供）：杜氏肌营养不良症（DMD）患者横纹肌退化的肺部并发症和其他并发症的治疗进展已使心肌病成为死亡的主要原因。 DMD 患者骨骼肌无力导致的活动受限常常掩盖了其他心肌疾病人群中常见的典型症状，导致疾病进展不受控制。如果不进行积极的筛查，DMD患者心脏病的首发表现可能是严重心力衰竭或心源性猝死。我们的团队和其他人使用心脏磁共振 (CMR) 检测到 DMD 患者在左心室射血分数 (EF) 降低之前的心肌纤维化。此外，通过 CMR 衍生的应变测量（收缩功能障碍的更敏感标记），我们发现每年都会发生亚临床衰退。认识到保留 EF 的纤维化导致人们认为具有“抗纤维化”作用的旧心脏药物可能对 DD 心肌病有益。一个订婚的家庭发起了一项筹款活动，推动了我们的假设的快速检验。随后，我们在开始日期后不到 12 个月的时间内发表了引人注目的临床前数据，表明对 DMD 小鼠模型进行醛固酮抑制加血管紧张素转换酶抑制剂 (ACEI) 的早期治疗可显着减少肌肉损伤并保留心脏和骨骼的肌肉功能肌肉。当前的指导方针提倡发起例如当 EF 低于正常值时，应使用血管紧张素转换酶抑制剂 (ACEI)，但我们的数据表明，早期治疗应该更有益。自 2011 年 8 月发表这项工作以来，我们已经取得了重大进展，这将使我们能够快速执行 3 个重要的后续步骤：i) 旨在确定营养不良心脏的最佳醛固酮拮抗剂的临床前研究； ii) 具有结构、功能和血清学终点的心脏临床试验； iii) 机制研究的重点是确定疗效途径，以优化 DMD 中所有受影响肌肉的未来治疗。为了解决这些关键问题，我们组建了一个强大的跨学科团队，对保存完好的 EF DMD 男孩进行醛固酮拮抗加 ACEI 的里程碑式患者研究，并进行平行小鼠实验，以精确确定不同横纹肌类型中的哪些核受体介导观察到的治疗效果。为了证明我们关于减轻临床前变化功效的假设，临床研究将使用最先进的亚临床收缩功能障碍和纤维化的非侵入性 CMR 生物标志物。这些数据将为处理这种毁灭性疾病的患者、家庭和医疗服务提供者提供急需的证据，证明现有药物（已用于儿童和成人的其他适应症）可以提供一种有效的治疗方法。潜在的心脏保护作用。临床前研究的成功执行将为合理设计治疗方法提供必要的见解，从而对减少 DMD 患者的死亡和残疾产生最大的影响。