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：
8894629
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 2017-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8894629
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 dysfunction 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 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）：Duchenne肌肉营养不良是一种严重的退化性肌肉疾病，其特征是10岁时失去行动，而在生命的第三个十年中死亡。除皮质类固醇外，没有其他治疗方法，它们具有限制使用持续时间的严重副作用。 DMD是由X连锁肌营养不良蛋白基因突变引起的。正在积极研究基因校正方法，但在不久的将来不太可能被广泛使用。现在迫切需要负担得起的肌肉变性的负担得起的治疗方法，直到有效的基因矫正技术广泛可用并具有成本效益为止。我们有强有力的概念证据证明，HMG CoA还原酶抑制剂辛伐他汀显着改善了DMD MDX小鼠模型中骨骼肌和心脏肌肉中营养不良的表型。这种新颖的发现可能被认为是出乎意料的，因为他汀类药物偶尔会引起肌病，因此禁忌用于肌肉疾病的个体（包括DMD）。然而，用辛伐他汀对MDX小鼠的长期治疗大大降低了血浆肌酸激酶水平，增加了diaphragm特异性力并改善心脏舒张功能。首先，我们将使用随机的，双盲，安慰剂对照的研究评估MDX小鼠中两种他汀类药物和rosuvastatin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和diaphragm和伸肌长肌的组织学异常。在第二个目标中，将研究他汀类药物在老年MDX小鼠中逆转心脏和隔膜功能障碍的能力。最后，我们将确定他汀类药物是否改善了严重营养不良的MDX的寿命：Utrophin双基因敲除小鼠。这些研究的目的是使用严格的方法来获得强大的数据，该方法支持他汀类药物的进一步临床发展作为对DMD和可能其他肌营养不良的治疗方法。