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

• 批准号: 8576223
• 负责人: Jill A Rafael-Fortney
• 金额: $ 69.95万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8576223
• 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; 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; 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; public health relevance; randomized trial; research study; screening; success; sudden cardiac death; therapeutic gene; translational medicine; treatment trial

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(申请人提供)：在治疗Duchenne肌营养不良症(DMD)患者的肺部和其他横纹肌恶化并发症方面的进展使心肌病成为导致死亡的主要原因。DMD患者由于骨骼肌无力而导致的行走受限往往掩盖了在其他患有心肌疾病的人群中出现的典型症状，从而允许疾病不受控制地发展。如果没有积极的筛查，DMD患者心脏病的第一个表现可能是严重的心力衰竭或心脏性猝死。我们的团队和其他人利用心脏磁共振(CMR)在左心室射血分数(EF)降低之前检测到DMD患者的心肌纤维化。此外，通过CMR衍生的应变测量，一个更敏感的收缩功能障碍的标志，我们发现了每年发生的亚临床下降。认识到保留EF的纤维化使人们产生了这样的想法，即据报道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，推动了对我们假设的快速测试。我们随后发表了不到12个月的临床前数据，显示早期使用醛固酮抑制加血管紧张素转换酶抑制剂(ACEI)治疗DMD小鼠模型可显著减少肌肉损伤，并保留心肌和骨骼肌的肌肉功能。目前的指南建议，当EF降至正常以下时，开始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下一步的3个关键步骤：i)旨在确定治疗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；以及iii)侧重于确定疗效途径的机制研究，以便优化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，对保存下来的EF DMD男孩进行了一项里程碑式的醛固酮拮抗剂加血管紧张素转换酶抑制的患者研究，并进行了平行的小鼠实验，以精确确定不同横纹肌类型中的哪些核受体介导了观察到的治疗效果。为了证明我们关于减轻临床前改变的有效性的假设，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非侵入性CMR生物标记物。这些数据将为处理这种毁灭性疾病的患者、家庭和提供者提供急需的证据，现有药物已经用于儿童和成人的其他适应症，提供了一种 潜在的心脏保护益处。临床前研究的成功实施将为合理设计治疗方案提供必要的见解，以最大限度地减少DMD患者的死亡和残疾。