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）：治疗Duchenne肌肉营养不良（DMD）患者的肺部肌肉恶化的并发症的进展使心肌病成为死亡率的主要原因。 DMD中由于骨骼肌无力而导致的行动有限，通常会掩盖其他患有心肌疾病的人群中典型的症状，从而使疾病进展不受组织。如果没有侵略性筛查，DMD患者的心脏病的首次表现可能是严重的心力衰竭或心脏猝死。我们的小组和其他人使用心脏磁共振（CMR）在左心室射血分数（EF）减少之前检测到DMD患者的心肌纤维化。同样，通过CMR衍生的应变测量，收缩功能障碍的更敏感的标志物，我们发现每年发生的亚临床下降。通过保留的EF识别纤维化，导致了这样一种想法，即据报道“抗纤维化”作用的旧心脏药物可能对DD心肌病有益。一个敬业的家庭发起了一项筹款活动，促进了我们假设的快速检验。随后，我们在开始日期的不到12个月内发表了显着的临床前数据，表明，具有醛固酮抑制剂的DMD小鼠模型以及转化酶抑制剂（ACEI）的血管紧张素（ACEI）可显着减少肌肉损伤，并在心脏和骨骼肌中保持肌肉功能。当前的指南主张启动，例如当EF低于正常水平时，血管紧张素转化酶抑制剂（ACEI），但我们的数据表明，早期的治疗应该更有益。自2011年8月发表这项工作以来，我们已经取得了重大进展，这将使我们能够迅速执行3个基本步骤：i）一项旨在识别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）一项机械研究，旨在定义功效途径，以优化对DMD中所有受影响肌肉的未来治疗。为了解决这些关键问题，我们组装了一个强大的跨学科团队，以执行具有里程碑意义的患者对醛固酮拮抗作用的患者研究以及在保存的EF DMD男孩中的ACEI和ACEI和平行小鼠实验中的ACEI，以精确定义不同条纹肌肉类型中的核受体介导观察到的治疗效果。在证明我们关于减弱临床前变化功效的假设时，临床研究将使用亚临床收缩功能障碍和纤维化的最先进的无创CMR生物标志物。这些数据将为患者，家庭和提供者提供急需的证据潜在的心脏保护益处。成功执行临床前研究将为治疗剂的合理设计提供必要的见解，从而对DMD患者的死亡和残疾产生最大的影响。