Evaluating a novel pathway for treatment of Duchenne muscular dystrophy

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岁时失去行动能力，并在生命的第三个十年死亡。除了皮质类固醇，没有其他治疗方法，但皮质类固醇有严重的副作用，限制了使用时间。DMD是由x连锁肌营养不良蛋白基因突变引起的。人们正在积极研究基因校正方法，但在不久的将来不太可能广泛使用。在有效的基因校正技术得到广泛应用并具有成本效益之前，我们迫切需要能够负担得起的减缓肌肉退化的治疗方法。我们有强有力的概念证明，HMG辅酶a还原酶抑制剂辛伐他汀可以显著改善mdx小鼠DMD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，他汀类药物禁止用于患有肌肉疾病的个体，包括DMD。然而，长期使用辛伐他汀治疗mdx小鼠可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，我们将通过随机、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。既定的方法将用于检查肌肉收缩功能的改善和膈肌和指长伸肌的组织学异常。在第二个目标中，他汀类药物逆转老年mdx小鼠心脏和膈功能障碍的能力将被研究。最后，我们将确定他汀类药物是否能改善严重营养不良的mdx:utrophin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，以支持他汀类药物作为DMD和其他肌肉营养不良症治疗的进一步临床开发。

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.