RNA Interference Inhibits DUX4-induced Muscle Toxicity In Vivo: Implications for a Targeted FSHD Therapy
RNA Interference Inhibits DUX4-induced Muscle Toxicity In Vivo: Implications for a Targeted FSHD Therapy
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DOI：
10.1038/mt.2012.68
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发表时间：
2012-07-01
影响因子：
12.4
通讯作者：
Harper, Scott Q.
中科院分区：
文献类型：
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作者：
Wallace, Lindsay M.;Liu, Jian;Harper, Scott Q.
面肩肩周肌营养不良症(FSHD)是最常见的遗传性肌肉疾病之一，目前尚无治疗方法。尽管FSHD可能会使人虚弱，但几乎没有努力开发有针对性的治疗方法。这种缺乏对有针对性的FSHD治疗的关注持续存在，因为参与这种疾病的基因和途径还不清楚。现在，在破译FSHD根本原因的努力开始20多年后，翻译的障碍终于降低了。具体地说，最近的几项研究支持FSHD发病机制模型，涉及肌病DUX4基因的过度表达。因此，抑制DUX4已成为治疗FSHD的一种有前途的治疗策略。在这项研究中，我们测试了一种基于临床前RNA干扰(RNAi)的DUX4基因沉默方法，作为FSHD的一种前瞻性治疗方法。我们发现，腺相关病毒(AAV)载体递送的治疗性microRNAs纠正了小鼠肌肉中DUX4相关的肌病。这些结果为通过抑制DUX4进行RNAi治疗FSHD提供了理论依据。2011年11月30日收到；2012年3月11日接受；2012年4月17日预售在线出版物。DOI：10.1038/mt.2012.68
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. Received 30 November 2011; accepted 11 March 2012; advance online publication 17 April 2012. doi:10.1038/mt.2012.68