Evaluating a novel pathway for treatment of Duchenne muscular dystrophy

描述(申请人提供)：Duchenne肌营养不良症是一种严重的退行性肌肉疾病，特征是10岁时失去行走能力，并在生命的第三个十年死亡。除了皮质类固醇外，没有其他治疗方法，因为它有严重的副作用，限制了使用时间。DMD是由X连锁的Dstrophin基因突变引起的。基因校正方法正在积极研究，但在不久的将来不太可能广泛使用。现在迫切需要负担得起的延缓肌肉退化的治疗方法，直到有效的基因纠正技术变得广泛可用和具有成本效益。我们有强有力的概念验证证据表明，HMG辅酶A还原酶抑制剂辛伐他汀显著改善DMD MDX小鼠模型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导致肌病，因此，他汀类药物被禁止用于患有肌肉疾病的个人，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，增加横隔膜比力，并改善心脏舒张期功能。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罗舒伐他汀在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和横隔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小鼠心脏和横隔膜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：utroin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治疗DMD和可能的其他肌营养不良症的进一步临床开发。

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.