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: 10026786
• 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/10026786
• 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; 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; 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; 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; recombinase-mediated cassette exchange; 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.

皮质类固醇是治疗多种形式的心力衰竭和慢性心力衰竭的重要药物。 炎症，总共影响了超过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。我们的实验室开发出了一流的 既能保护心脏又能消炎的游离类固醇。我们在中国的工作 DMD的MDX小鼠模型对于将这种药物--艾美龙--推向DMD临床试验(现已进入阶段)至关重要 2B)。在早期的细胞和动物研究中，呋喃西林在避免关键副作用的同时显示出抗炎效果 效果。随后，我们发现了新的药物活性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的一个特征(由丢失 肌营养不良症(Dystrophin)和较轻微的肌肉疾病Becker肌营养不良症(dystrophin在框内缺失)。AS 有希望的新疗法正在开发中，寻求将严重的DMD基因型转变为较轻的Becker- 像表型一样，治疗营养不良的心脏的重要性应该增加，因为心肌病是主要的 贝克尔死亡的原因。展望未来，重要的是解决有关以下方面的知识差距 选择性类固醇的机制，特定类固醇受体在心脏中的作用，以及类固醇对 贝克尔式的心。这一知识很重要，因为心肌病是导致DMD死亡的主要原因 而且目前的皮质类固醇药物的安全性有问题。 我们的长期目标是剖析类固醇信号的机制，这些机制可以有选择地针对改善 慢性儿科疾病的治疗。这可以极大地改善DMD的结果，同时也会影响 心脏、肌肉和炎症性疾病的群体要大得多。这笔赠款的目的是剖析 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，可以通过结合细胞培养、 受体突变、组织特异性基因敲除、微肌营养不良蛋白基因治疗和动物模型系统。我们 提出11种β-羟基类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。我们的理论基础是，识别皮质类固醇机制 可选择性靶向将为改善DMD和其他疾病的治疗提供基础 心力衰竭或慢性炎症。