Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth.
Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth.
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DOI：
10.1038/mtna.2016.55
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发表时间：
2016-08-02
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短干扰RNA(SiRNAs)是基因沉默的一种有价值的工具，在靶点验证和治疗方面都有应用。最近在提高效力和特异性、降低毒性和免疫刺激方面取得了许多进展。然而，将siRNA运送到各种组织仍然是这项技术的障碍。到目前为止，将siRNA输送到肌肉中的方法仅限于局部给药或临床应用潜力有限的方法。我们报道了一种针对肌肉特异性基因myostatin(MSTN)的高度化学修饰的胆固醇偶联siRNA系统地输送到小鼠的各种肌肉中。在一次静脉注射后，我们观察到骨骼肌中MSTN mRNA被击倒85-95%，循环中MSTN蛋白减少65%，持续21天。这种水平的MSTN基因敲除还伴随着对骨骼肌的功能影响，动物表现出肌肉质量、大小和力量的增加。这里描述的胆固醇结合的siRNA平台可能对治疗各种肌肉疾病具有重要意义，包括肌肉萎缩性疾病、肌肉营养不良和II型糖尿病。
Short interfering RNAs (siRNAs) are a valuable tool for gene silencing with applications in both target validation and therapeutics. Many advances have recently been made to improve potency and specificity, and reduce toxicity and immunostimulation. However, siRNA delivery to a variety of tissues remains an obstacle for this technology. To date, siRNA delivery to muscle has only been achieved by local administration or by methods with limited potential use in the clinic. We report systemic delivery of a highly chemically modified cholesterol-conjugated siRNA targeting muscle-specific gene myostatin (Mstn) to a full range of muscles in mice. Following a single intravenous injection, we observe 85–95% knockdown of Mstn mRNA in skeletal muscle and >65% reduction in circulating Mstn protein sustained for >21 days. This level of Mstn knockdown is also accompanied by a functional effect on skeletal muscle, with animals showing an increase in muscle mass, size, and strength. The cholesterol-conjugated siRNA platform described here could have major implications for treatment of a variety of muscle disorders, including muscular atrophic diseases, muscular dystrophy, and type II diabetes.
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影响因子：
12.4
作者：
Hagstrom, JE;Hegge, J;Wolff, JA
通讯作者：
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3.5
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20.1
作者：
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通讯作者：
Rosenzweig, Anthony