Mechanisms of corticosteroids in dystrophic cardiomyopathy

皮质类固醇治疗营养不良性心肌病的机制

• 批准号: 10669137
• 负责人: Christopher Ryan Heier
• 金额: $ 7.6万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669137
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Asparagine; Becker Muscular Dystrophy; Binding; Biological Models; Cardiomyopathies; Cell Culture Techniques; Cells; Childhood; Chronic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Corticosteroid Receptors; Data; Disease; Dissociation; Drug Prescriptions; Drug Targeting; Duchenne muscular dystrophy; Dystrophin; Etiology; Fibrosis; Functional disorder; Gene Expression; Genes; Genotype; Glucocorticoid Receptor; Goals; Grant; Heart; Heart Diseases; Heart failure; Human; Hydroxysteroids; Immune; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; Ligands; LoxP-flanked allele; Mediating; Methodology; MicroRNAs; Mineralocorticoid Receptor; Modeling; Molecular; Mus; Muscle; Muscular Dystrophies; Mutation; Myocardium; Myopathy; Outcome; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Physiological; Point Mutation; Positioning Attribute; Prednisone; Receptor Activation; Role; Safety; Serum; Signal Transduction; Skeletal Muscle; Steroid Receptors; Steroids; Structure; System; Testing; Tissues; Transactivation; Work; antagonist; cardioprotection; clinically relevant; drug development; drug discovery; dystrophic cardiomyopathy; effective therapy; exon skipping therapy; gene therapy; improved; improved outcome; mdx mouse; micro-dystrophin; mortality; mouse model; novel; novel therapeutics; pharmacologic; receptor; restoration; side effect; standard of care; tool

Corticosteroids provide an important drug class for treatment of numerous forms of heart failure and chronic inflammation, together affecting over 432 million people. In Duchenne muscular dystrophy (DMD), drugs that target corticosteroid receptors are used to treat heart and skeletal muscle. Our lab developed a first-in-class dissociative steroid that shows efficacy as both a heart-protective and anti-inflammatory drug. Our work in the mdx mouse model of DMD was critical for moving this drug, vamorolone, into DMD clinical trials (now in Phase 2b). In early cell and animal studies, vamorolone showed anti-inflammatory efficacy while avoiding key side effects. Subsequently, we discovered new readouts of drug activity and important impacts of corticosteroids on dystrophic hearts. Cardiomyopathy is a feature of both the severe muscle disease DMD (caused by loss of dystrophin) and the milder muscle disease Becker muscular dystrophy (dystrophin in-frame deletions). As promising new therapies are being developed that seek to convert severe DMD genotypes into milder Becker- like phenotypes, importance of treating dystrophic hearts should grow because cardiomyopathy is the leading cause of Becker mortality. Moving forward, it will be important to address knowledge gaps regarding the mechanisms of selective steroids, roles of specific steroid receptors in the heart, and impacts of steroids on Becker-like hearts. This knowledge is important because cardiomyopathy is a leading cause of DMD mortality and current corticosteroids have problematic safety profiles. Our long-term goal is to dissect mechanisms of steroid signaling that can be selectively targeted to improve treatment of chronic pediatric diseases. This can greatly improve outcomes for DMD in a way that also impacts much larger groups of heart, muscle and inflammatory diseases. The objective of this grant is to dissect mechanisms of corticosteroid receptors that impact dystrophic cardiomyopathy. The advanced expertise and tools developed by our lab place us in a unique position to accomplish this using a combination of cell culture, receptor mutation, tissue-specific knockout, micro-dystrophin gene therapy, and animal model systems. We propose the central hypothesis that 11β-hydroxysteroid agonists activate receptor transactivation to drive progression of dystrophic heart pathology. Our rationale is that identifying corticosteroid mechanisms which can be selectively targeted will provide a basis for the improved treatment of DMD and other diseases with heart failure or chronic inflammation.

皮质类固醇提供了一种重要的药物类，用于治疗多种形式的心力衰竭和慢性 炎症共同影响超过4.32亿人。在Duchenne肌肉营养不良（DMD）中，药物 靶皮质类固醇受体用于治疗心脏和骨骼肌。我们的实验室开发了一流的 解离类固醇既表现为心脏保护和抗炎药。我们在 DMD的MDX小鼠模型对于将这种药物（Vamorone）移入DMD临床试验至关重要（现在 2b）。在早期细胞和动物研究中，瓦莫洛龙显示出抗炎效率，同时避免了关键方面 效果。随后，我们发现了对药物活性的新读数以及皮质类固醇的重要影响 营养不良的心。心肌病是严重肌肉疾病DMD的一个特征（由于失去 肌营养不良蛋白）和米勒肌肉疾病贝克尔肌肉营养不良（肌营养不良蛋白障碍缺失）。作为 正在开发有希望的新疗法，试图将严重的DMD基因型转化为Miller Becker- 像表型一样，治疗营养不良心脏的重要性应该增长，因为心肌病是领先的 贝克尔死亡率的原因。向前迈进，解决有关的知识差距很重要 选择性类固醇的机制，特定类固醇受体在心脏中的作用以及类固醇的影响 贝克尔般的心。这种知识很重要，因为心肌病是DMD死亡率的主要原因 当前的皮质类固醇具有问题的安全性。 我们的长期目标是剖析可以选择性靶向的类固醇信号的机制 治疗慢性小儿疾病。这可以大大改善DMD的结果，从而影响DMD 更大的心脏，肌肉和炎症性疾病。这笔赠款的目的是剖析 影响营养不良心肌病的皮质类固醇受体的机制。高级专业知识和 我们的实验室开发的工具将我们处于独特的位置，可以使用细胞培养的组合来实现这一目标， 受体突变，组织特异性基因敲除，微肌营养蛋白基因治疗和动物模型系统。我们 提出一个中心假设，即11β-羟基固醇激动剂激活受体反式激活以驱动 营养不良心脏病理的进展。我们的理由是识别皮质类固醇机制 可以选择性地定位将为改进DMD治疗和其他疾病的治疗提供基础 心力衰竭或慢性炎症。