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

基本信息

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
项目类别：
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

项目摘要

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 10 岁时丧失行走能力，并在 30 岁时死亡。除了皮质类固醇之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得到广泛使用。现在迫切需要经济实惠的减缓肌肉退化的治疗方法，直到有效的基因校正技术得到广泛应用且具有成本效益。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着改善 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出乎意料的，因为已知他汀类药物偶尔会引起肌病，因此禁止用于患有肌肉疾病（包括 DMD）的个体。然而，长期用辛伐他汀治疗 mdx 小鼠可显着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、安慰剂对照研究来评估两种他汀类药物（辛伐他汀和瑞舒伐他汀）在 mdx 小鼠中的剂量反应。已建立的方法将用于检查肌肉收缩功能的改善以及膈肌和趾长伸肌的组织学异常。第二个目标是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可以延长严重营养不良的 mdx:utropin 双敲除小鼠的寿命。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 和可能的其他肌营养不良症治疗的进一步临床开发。