Targeting nuclear RNA for in vivo correction of myotonic dystrophy.
Targeting nuclear RNA for in vivo correction of myotonic dystrophy.
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DOI：
10.1038/nature11362
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发表时间：
2012-08-02
期刊：
影响因子：
64.8
通讯作者：
Thornton, Charles A.
中科院分区：
文献类型：
--
作者：
Wheeler, Thurman M.;Leger, Andrew J.;Pandey, Sanjay K.;MacLeod, A. Robert;Nakamori, Masayuki;Cheng, Seng H.;Wentworth, Bruce M.;Bennett, C. Frank;Thornton, Charles A.
反义寡核苷酸（ASO）有望在涉及RNA或蛋白质功能获得的疾病中实现基因特异性敲除。在遗传性退行性疾病强直性肌营养不良1型（DM 1）中，来自突变等位基因的转录物含有扩增的CUG重复序列并保留在细胞核中。突变RNA发挥毒性功能获得性，使其成为治疗性ASO的适当靶标。然而，尽管在阿索化学和设计方面有所改进，但是由于在许多组织（包括骨骼肌和心肌）中的摄取不足以使靶mRNA沉默，所以ASO的全身使用受到限制。在这里，我们表明，核保留转录含有扩大CUG（CUGexp）重复是非常敏感的反义沉默。在DM 1转基因小鼠模型中，全身给予ASO导致骨骼肌中CUGexp RNA的快速敲低，纠正了疾病的生理学、组织病理学和转录组学特征。这种效果在停止治疗后可持续长达一年。全身施用的ASO也有效地用于肌肉敲低Malat-1，Malat-1是一种保留在细胞核中的长非编码RNA（lncRNA）。这些结果提供了一个通用的策略，以纠正RNA获得的功能，并调节扩展的重复序列，lncRNA，和其他转录与延长核驻留的表达。
Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat and are retained in the nucleus. The mutant RNA exerts a toxic gain-of-function, 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 mRNAs. Here we show that nuclear-retained transcripts containing expanded CUG (CUGexp) repeats are extraordinarily 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 one year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat-1, a long noncoding RNA (lncRNA) that is retained in the nucleus. These results provide a general strategy to correct RNA gain-of-function and modulate the expression of expanded repeats, lncRNAs, and other transcripts with prolonged nuclear residence.
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