Nature：利用反义RNA去除肌细胞中毒性RNA有望逆转肌营养不良症

在一项新研究中，来自美国罗切斯特大学、伊希斯制药公司(Isis Pharmaceuticals Inc.)和健赞公司(Genzyme)的研究人员通过除去肌细胞中毒性RNA的积累而逆转小鼠强直性肌营养不良症(myotonic muscular dystrophy)的症状。相关研究结果于2012年8月2日发表在Nature期刊上。

强直性肌营养不良症是一种遗传性缺陷疾病。在这种疾病中，遗传缺陷导致一种异常的mRNA产生，并积累在细胞核中，妨碍并阻止其他蛋白发挥作用。这些蛋白之一就是MBNL1，它有助于产生对肌肉电控制比较重要的氯离子通道。当这种过程遭受阻碍时，肌肉发送错误的电信号，从而导致疾病症状产生。

在这项研究中，研究人员研究了这种缺陷产生的根源，利用一种将RNA切割成碎片的酶开展研究。为此，他们构建出合成出人工化合物---经过化学修饰的DNA短片段---，并且这种短片段能够结合到这种毒性的RNA(即异常RNA积累在细胞核中，从而导致细胞过程发生差错)上，并且对它进行修饰，从而使得它能够被身体自己的一种酶---核糖核酸酶H (RNase H)---所摧毁。另外，因为这种化合物也被称作反义药物(antisense compound)，这是因为它的遗传密码与靶RNA链(即正义链)相互补。

利用这种最为有效的化合物，研究人员通过给小鼠注射这种实验性药物，每周注射两次，总共4周，研究人员发现这种疾病的症状减少高达1年。小鼠身上的疾病症状被逆转：毒性RNA水平下降80%以上；肌肉硬度显著性下降；肌肉的显微结构得到改善；肌肉中的电信号恢复正常。

不过研究人员说，尽管这项研究在治疗强直性肌营养不良症上取得的一次鼓舞人心的进步，但是若要说这种方法在病人体内有效仍然为时太早。不过，他们仍然保持谨慎乐观，这是因为在小鼠模式动物中，这种药物能够极其显著地逆转这种疾病。

本文编译自A step forward toward muscular dystrophy treatment: 'Antisense' compound rids muscle cells of toxic RNA

doi: 10.1038/nature11362
PMC:
PMID:

Targeting nuclear RNA for in vivo correction of myotonic dystrophy

Thurman M. Wheeler, Andrew J. Leger, Sanjay K. Pandey, A. Robert MacLeod, Masayuki Nakamori, Seng H. Cheng, Bruce M. Wentworth, C. Frank Bennett & Charles A. Thornton

Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function effects. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat1, 2, 3 and are retained in the nucleus4, 5. The mutant RNA exerts a toxic gain-of-function effect6, making it an appropriate target for therapeutic ASOs. However, despite improvements in ASO chemistry and design, systemic use of ASOs is limited because uptake in many tissues, including skeletal and cardiac muscle, is not sufficient to silence target messenger RNAs7, 8. Here we show that nuclear-retained transcripts containing expanded CUG (CUGexp) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUGexp RNA in skeletal muscle, correcting the physiological, histopathologic and transcriptomic features of the disease. The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1, a long non-coding RNA (lncRNA) that is retained in the nucleus9. These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and other transcripts with prolonged nuclear residence.