Evaluating a novel pathway for treatment of Duchenne muscular dystrophy

评估治疗杜氏肌营养不良症的新途径

• 批准号: 8772274
• 负责人: STANLEY C FROEHNER
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772274
• 关键词: 10 year old; Adrenal Cortex Hormones; Adverse effects; Age; Age-Months; Biochemical; Blood; Blood specimen; Cardiac; Cardiomyopathies; Cell Nucleus; Cessation of life; Child; Childhood; Clinical; Creatine Kinase; Data; Development; Diet; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Duchenne muscular dystrophy; Dystrophin; Echocardiography; Effectiveness; Exercise; Fiber; Fibrosis; Food; Functional disorder; Future; Genes; Goals; Half-Life; Health; High Density Lipoproteins; Hindlimb; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Individual; Inflammation; Knockout Mice; LDL Cholesterol Lipoproteins; Life; Link; Liver; Longevity; Measures; Metabolism; Methodology; Methods; Modeling; Mus; Muscle; Muscle Fatigue; Muscular Dystrophies; Mutation; Myocardial tissue; Myocardium; Myopathy; Pathway interactions; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Placebo Control; Plasma; Population; Preclinical Testing; Predisposition; Randomized; Respiratory Diaphragm; Running; Simvastatin; Skeletal Muscle; Techniques; Testing; Therapeutic Agents; Tissues; Ultrasonography; Utrophin; Variant; Very low density lipoprotein; Weaning; aged; base; boys; cost effective; extensor digitorum; gene correction; hypercholesterolemia; improved; in vivo; mdx mouse; mouse model; muscle degeneration; novel; novel therapeutic intervention; novel therapeutics; placebo controlled study; pre-clinical; public health relevance; response; rosuvastatin; uptake

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy is a severe degenerative muscle disease characterized by loss of ambulation at 10 years of age, and death in the third decade of life. There is no treatment other than corticosteroids, which have severe side effects that limit the duration of use. DMD is caused by mutations in the X-linked dystrophin gene. Gene correction approaches are being studied aggressively but are unlikely to be in wide use in the near future. Affordable treatments that slow muscle degeneration are urgently needed now until effective gene correction techniques become widely available and cost effective. We have robust proof-of-concept evidence that the HMG CoA-reductase inhibitor, Simvastatin, markedly improves the dystrophic phenotype in skeletal and cardiac muscle in the mdx mouse model of DMD. This novel finding might be considered unexpected since statins are known to occasionally cause myopathy and, as a consequence, are contraindicated for use in individuals with muscle diseases, including DMD. However, long-term treatment of mdx mice with Simvastatin dramatically reduces plasma creatine kinase levels, increases diaphragm specific force and improves cardiac diastolic function. First, we will evaluate the dose response of two statins, Simvastatin and Rosuvastatin, in mdx mice using randomized, double blind, placebo-controlled studies. Established methods will be used to examine improvements in muscle contractile function and histological abnormalities in diaphragm and extensor digitorum longus muscles. In a second aim, the ability of statins to reverse cardiac and diaphragm dysfunction in aged mdx mice will be studied. Finally, we will determine if statins improve the lifespan of severely dystrophic mdx:utrophin double knockout mice. The goal of these studies is to obtain robust data, using rigorous methodology, that support further clinical development of statins as a treatment of DMD and possibly other muscular dystrophies.

描述（由申请人提供）：杜氏肌营养不良症是一种严重的退行性肌肉疾病，其特征是在10岁时丧失骨骼肌，并在30岁时死亡。除了皮质类固醇外，没有其他治疗方法，皮质类固醇具有严重的副作用，限制了使用的持续时间。DMD是由X连锁肌营养不良蛋白基因突变引起的。基因校正方法正在积极研究，但不太可能在不久的将来被广泛使用。现在迫切需要负担得起的减缓肌肉退化的治疗方法，直到有效的基因校正技术变得广泛可用且具有成本效益。我们有强有力的概念验证证据表明，HMG CoA还原酶抑制剂辛伐他汀可显著改善DMD mdx小鼠模型中骨骼肌和心肌的营养不良表型。这一新发现可能被认为是意外的，因为他汀类药物已知偶尔会引起肌病，因此，禁忌用于肌肉疾病（包括DMD）患者。然而，用辛伐他汀长期治疗mdx小鼠显著降低血浆肌酸激酶水平，增加膈肌比力并改善心脏舒张功能。首先，我们将使用随机、双盲、安慰剂对照研究评价两种他汀类药物（辛伐他汀和瑞舒伐他汀）在mdx小鼠中的剂量反应。建立的方法将被用来检查改善肌肉收缩功能和组织学异常的隔膜和趾长伸肌肌肉。在第二个目标中，将研究他汀类药物逆转老年mdx小鼠心脏和膈肌功能障碍的能力。最后，我们将确定他汀类药物是否能改善严重营养不良mdx：utrophin双基因敲除小鼠的寿命。这些研究的目标是使用严格的方法获得可靠的数据，支持他汀类药物作为DMD和其他可能的肌营养不良症治疗的进一步临床开发。