Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
Mol Ther. 2012 Jul;20(7):1417-23. doi: 10.1038/mt.2012.68. Epub 2012 Apr 17.
No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack of focus on targeted FSHD therapy perpetuated because the genes and pathways involved in the disorder were not understood. Now, more than 2 decades after efforts to decipher the root cause of FSHD began, this barrier to translation is finally lowering. Specifically, several recent studies support an FSHD pathogenesis model involving overexpression of the myopathic DUX4 gene. DUX4 inhibition has therefore emerged as a promising therapeutic strategy for FSHD. In this study, we tested a preclinical RNA interference (RNAi)-based DUX4 gene silencing approach as a prospective treatment for FSHD. We found that adeno-associated viral (AAV) vector-delivered therapeutic microRNAs corrected DUX4-associated myopathy in mouse muscle. These results provide proof-of-principle for RNAi therapy of FSHD through DUX4 inhibition.
尚无针对面肩肱型肌营养不良症（FSHD）的治疗方法，FSHD 是最常见的遗传性肌肉疾病之一。尽管 FSHD 可能使人衰弱，但针对这种疾病的靶向治疗方法却很少得到开发。这种对 FSHD 靶向治疗缺乏关注的情况一直持续存在，原因是人们并不了解导致该病的基因和途径。现在，在开始破译 FSHD 根本原因 20 多年后，这一转化障碍终于得到了克服。具体来说，最近的几项研究支持一种 FSHD 发病机制模型，该模型涉及肌病相关 DUX4 基因的过度表达。因此，抑制 DUX4 已成为治疗 FSHD 的一种很有前途的治疗策略。在这项研究中，我们测试了一种基于腺相关病毒（AAV）载体的 RNA 干扰（RNAi）靶向 DUX4 基因沉默方法，作为治疗 FSHD 的一种有前景的方法。我们发现，腺相关病毒载体递送的治疗性 microRNAs 纠正了小鼠肌肉中的 DUX4 相关肌病。这些结果为通过抑制 DUX4 进行 FSHD 的 RNA 治疗提供了原理性证据。
