Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

描述（由申请人提供）：治疗杜氏肌营养不良（DMD）患者横纹肌恶化的肺部和其他并发症的进展使心肌病成为死亡的主要原因。DMD患者由于骨骼肌无力导致的活动受限常常掩盖了其他心肌疾病患者的典型症状，从而导致疾病未受控制的进展。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源性猝死。本研究小组和其他研究人员利用心脏磁共振（CMR）检测了左心室射血分数（EF）降低前DMD患者的心肌纤维化。此外，通过cmr衍生的应变测量，一种更敏感的收缩功能障碍标志物，我们发现亚临床衰退每年都会发生。通过保存的EF识别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。一个积极参与的家庭发起了一项筹款活动，推动了我们假设的快速验证。我们随后在研究开始后不到12个月的时间里发表了显著的临床前数据，表明在DMD小鼠模型中，醛固酮抑制加血管紧张素转换酶抑制剂（ACEI）的早期治疗显著减少了肌肉损伤，并保留了心脏和骨骼肌的肌肉功能。目前的指南提倡在EF低于正常值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月这项工作发表以来，我们已经取得了重大进展，这将使我们能够快速执行三个重要的下一步：1)临床前研究，旨在确定治疗营养不良心脏的最佳醛固酮拮抗剂；Ii)具有结构、功能和血清学终点的心脏临床试验；iii)一项机制研究侧重于确定疗效途径，以优化未来对DMD所有受影响肌肉的治疗。为了解决这些关键问题，我们组建了一支强大的跨学科团队，在保存完好的EF DMD男孩中进行了一项具有里程碑意义的醛固酮拮抗剂加ACEI的患者研究，并进行了平行小鼠实验，以精确定义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无创CMR生物标志物。这些数据将为处理这一毁灭性疾病的患者、家庭和提供者提供急需的证据，证明现有药物——已经用于儿童和成人的其他适应症——提供了一种有效的治疗方法

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.