Abstract：
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with 4 microdystrophin constructs (3 in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using AAV doses comparable with those in clinical trials. We achieved high levels of microdystrophin expression in striated muscles with cardiac expression approximately 10-fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease occurred with 2 of the microdystrophins. The detrimental cardiac effect appears to be caused by variable competition (dependent on microdystrophin design and expression level) between microdystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-microdystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, these findings suggest that microdystrophin treatments need to avoid excessively high levels of expression in the heart and that cardiac function should be carefully monitored in these patients.
摘要：
对于患有杜兴氏肌营养不良症（DMD）的个体，正在进行提供高剂量表达截短的肌营养不良蛋白分子（微肌营养不良蛋白）的腺相关病毒（AAV）的临床试验。我们使用四个微肌营养不良蛋白构建体（临床试验中的三个和最大临床构建体的变体）检查了该策略的效率和功效，在严重的DMD小鼠模型中，使用与临床试验中使用的AAV剂量相当的AAV。我们在横纹肌中实现了高水平的微肌营养不良蛋白表达，心脏表达比骨骼肌中观察到的高〜10倍。重要的,虽然不完整，观察到骨骼肌疾病的纠正。令人惊讶的是,两种微肌营养不良蛋白导致心脏疾病进展加速致死.对心脏的有害影响似乎是由高水平的微肌营养不良蛋白引起的，该高水平的微肌营养不良蛋白导致心肌细胞膜上的微肌营养不良蛋白和肌萎缩蛋白之间的可变竞争（取决于微肌营养不良蛋白的设计）。也可能存在来自蛋白质降解的过载的贡献。这些观察对于目前正在用AAV-微肌营养不良蛋白疗法治疗的患者的意义尚不清楚,因为在DMD心脏中实现的表达水平是未知的。然而,这表明，微肌营养不良蛋白治疗需要避免在心脏中表达水平过高，因此应仔细监测这些患者的心功能。
