cGMP Phosphodiesterase Inhibitors in a Mouse Model of Duchenne Muscular Dystrophy

描述（由申请人提供）：尽管肌营养不良症是由许多不同基因的突变引起的，但它们有几个共同的特征：肌肉质量减少，炎症和纤维化，以及渐进式再生失败。最终，基因替换或基因矫正将导致治愈，但这些方法的常规应用可能还需要几十年的时间。减缓肌肉退化进展的治疗方法的发展将改善质量和寿命，并允许在疾病的更晚期进行治疗。在这个应用中，我们建议测试环核苷酸磷酸二酯酶（PDE）抑制剂在减缓营养不良肌肉退行性变过程中的功效。PDE抑制剂是环GMP （cGMP）介导途径的关键调节剂，已被证明是治疗多种人类疾病的有效药物靶点，包括炎症性气道疾病、间歇性跛行、复发性中风和勃起功能障碍。在压力诱导小鼠模型中，PDE抑制剂，特别是针对PDE5的抑制剂，可以减少心脏肥大和纤维化。我们有新的证据表明，一氧化氮刺激的高尔基体cGMP通路在mdx小鼠骨骼肌中被破坏。我们将验证给mdx小鼠注射PDE抑制剂会减缓骨骼肌退化进程的假设。初步证据表明，在饮用水中施用西地那非（一种PDE5抑制剂）可改善营养不良表型。最终，通过调节cGMP通路刺激肌肉生长和修复的基因或细胞治疗方法与药物治疗相结合，可能是治疗各种遗传来源的肌肉营养不良的有效方法。

DESCRIPTION (provided by applicant): Despite the fact that muscular dystrophies are caused by mutations in numerous different genes, they share several common features: loss of muscle mass, inflammation and fibrosis, and progressive failure to regenerate. Ultimately, gene replacement or correction will lead to cures, but routine application of these approaches is likely to be decades away. The development of treatments that slow the progression of muscle degeneration will improve the quality and length of life and permit treatment at more advanced stages of the disease. In this application, we propose to test the efficacy of cyclic nucleotide phosphodiesterase (PDE) inhibitors in slowing the degeneration process in dystrophic muscle. PDE inhibitors are key modulators of cyclic GMP (cGMP) mediated pathways and have proven to be effective drug targets in treating several human diseases, including inflammatory airway diseases, intermittent claudication, recurrent stroke and erectile dysfunction. PDE inhibitors, particularly those targeted at PDE5, reduce cardiac hypertrophy and fibrosis in a pressure induced mouse model. We have new evidence that a nitric oxide-stimulated cGMP pathway on the Golgi complex is disrupted in skeletal muscle of mdx mice. We will test the hypothesis that administration of PDE inhibitors to mdx mice will slow the progression of skeletal muscle degeneration. Preliminary evidence suggests that sildenafil, a PDE5 inhibitor, administered in the drinking water improves the dystrophic phenotype. Ultimately, gene or cell therapy approaches combined with drug treatments that stimulate muscle growth and repair by modulation of cGMP pathways could be an effective treatment for muscular dystrophies of various genetic origins. The research proposed here will test FDA-approved drugs (phosphodiesterase inhibitors) for their ability to slow the progression of muscle degeneration in muscular dystrophy. If efficacious, these drugs could quickly be tested for this use in humans since they have already been approved for treatment of other diseases. They may be useful in many different types of muscular dystrophies by improving muscle health and prolonging survival time.