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: 10462498
• 负责人: Christopher Ryan Heier
• 金额: $ 44.63万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462498
• 关键词: Address; Adrenal Cortex Hormones; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Archives; Asparagine; Becker Muscular Dystrophy; Binding; Biological Models; Cardiomyopathies; Cell Culture Techniques; Cells; Childhood; Chronic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Corticosteroid Receptors; Cre lox recombination system; Data; Disease; Drug Prescriptions; Drug Targeting; Duchenne muscular dystrophy; Dystrophin; Etiology; Fibrosis; Functional disorder; Gene Expression; Genes; Genotype; Glucocorticoid Receptor; Goals; Grant; Heart; Heart failure; Human; Hydroxysteroids; Immune; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; Ligands; Mediating; Methodology; MicroRNAs; Mineralocorticoid Receptor; Modeling; Molecular; Mus; Muscle; Muscular Dystrophies; Mutation; Myocardium; Myopathy; Outcome; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Physiological; Point Mutation; Positioning Attribute; Prednisone; Receptor Activation; Role; Safety; Serum; Signal Transduction; Skeletal Muscle; Steroid Receptors; Steroids; Structure; 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; 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.

皮质类固醇为治疗多种形式的心力衰竭和慢性心力衰竭提供了重要的药物类别。 炎症，共同影响超过4.32亿人。在杜氏肌营养不良症（DMD）中， 靶向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种 游离类固醇，显示出作为心脏保护和抗炎药物的功效。我们搞好 DMD的mdx小鼠模型对于将这种药物vamorolone转移到DMD临床试验中至关重要（目前处于第三阶段）。 2b）。在早期的细胞和动物研究中，vamorolone显示出抗炎功效，同时避免了关键的一面， 方面的影响.随后，我们发现了药物活性的新读数和皮质类固醇对 营养不良的心脏心肌病是严重的肌肉疾病DMD（由于缺乏 肌营养不良蛋白）和较温和的肌肉疾病贝克尔肌营养不良症（肌营养不良蛋白框内缺失）。作为 正在开发有希望的新疗法，试图将严重的DMD基因型转化为较温和的Becker- 像表型一样，治疗营养不良心脏的重要性应该增加，因为心肌病是主要的 贝克死亡的原因。展望未来，必须解决在以下方面的知识差距： 选择性类固醇的机制，心脏中特定类固醇受体的作用，以及类固醇对 贝克式心脏这方面的知识很重要，因为心肌病是DMD死亡的主要原因 目前的皮质类固醇的安全性存在问题。 我们的长期目标是剖析类固醇信号传导的机制，可以选择性地靶向改善 治疗慢性儿科疾病。这可以极大地改善DMD的结果， 更多的心脏、肌肉和炎症疾病。这项资助的目的是 皮质类固醇受体影响营养不良性心肌病的机制。先进的专业知识和 我们实验室开发的工具使我们处于一个独特的位置，可以使用细胞培养， 受体突变、组织特异性敲除、微肌营养不良蛋白基因治疗和动物模型系统。我们 提出了中心假设，即11β-羟基类固醇激动剂激活受体反式激活， 营养不良性心脏病理学的进展。我们的基本原理是，确定皮质类固醇的机制， 可选择性靶向治疗将为改善DMD和其他疾病的治疗提供基础， 心力衰竭或慢性炎症。