Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy.
Mol Ther. 2011 Nov;19(11):2055-64. doi: 10.1038/mt.2011.153. Epub 2011 Aug 9.
Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.
鉴于需要以全身性方式消除致病基因产物，治疗显性遗传性肌肉疾病仍然是一项艰巨的任务。我们在这里展示了一种可能的方法，即在面肩肱型肌营养不良症（FSHD）的小鼠模型中逆转显性肌肉疾病。FSHD 是一种常见的肌肉疾病，与位于 4 号染色体 4q35 上的 D4Z4 大片段重复数减少后复杂的表观遗传事件级联有关。已经检查了几个 4q35 基因在疾病中的作用，包括 FRG1。FRG1 的过表达会导致转基因小鼠出现与 FSHD 相关的特征，而 FRG1 小鼠目前是唯一可用的 FSHD 小鼠模型。在这里，我们展示了在疾病发作后，全身性递送 FRG1 小鼠中的 RNA 干扰表达盒，可导致剂量依赖性的长期 FRG1 下调，而没有毒性迹象。组织学特征包括中心核纤维、纤维大小减小、纤维化、脂肪细胞积累和炎症均得到显著改善。FRG1 mRNA 下调导致肌肉功能的显著恢复。通过 RNA 干扰（RNAi）表达盒重新设计，我们的方法可适用于靶向任何致病基因，为人类显性肌肉疾病的长期全身性治疗提供了可行的选择。
