Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by an expanded CTG repeat in the 3′ UTR of the dystrophia myotonica protein kinase (DMPK) gene. Short, DNA-based antisense oligonucleotides termed gapmers are a promising strategy to degrade toxic CUG expanded repeat (CUG_exp) RNA. Nucleoside analogs are incorporated to increase gapmer affinity and stability; however, some analogs also exhibit toxicity. In this study, we demonstrate that the 2′,4′-BNA^NC[NMe] (BNA^NC) modification is a promising nucleoside analog with high potency similar to 2′,4′-LNA (LNA). BNA^NC gapmers targeting a nonrepetitive region of the DMPK 3′ UTR show allele-specific knockdown of CUG_exp RNA and revert characteristic DM1 molecular defects including mis-splicing and accumulation of RNA foci. Notably, the BNA^NC gapmers tested in this study did not induce caspase activation, in contrast to a sequence matched LNA gapmer. This study indicates that BNA^NC gapmers warrant further study as a promising RNA targeting therapeutic.

中文翻译：

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BNA ^NC Gapmers还原拼接，并减少强直性营养不良细胞中低毒性的RNA灶。

1型强直性肌营养不良症（DM1）是由肌营养不良症肌强直蛋白激酶（DMPK）基因的3'UTR中的CTG重复序列扩增引起的多系统疾病。短的，基于DNA的反义寡核苷酸（称为间隔体）是降解有毒CUG扩展重复（CUG _exp）RNA的有前途的策略。掺入核苷类似物以增加gapmer亲和力和稳定性；但是，某些类似物也具有毒性。在这项研究中，我们证明2'，4'-BNA ^NC [NMe]（BNA ^NC）修饰是一种有前途的核苷类似物，具有与2'，4'-LNA（LNA）相似的高效能。靶向DMPK 3'UTR非重复区域的BNA ^NC间隙聚体显示CUG的等位基因特异性敲低_exp RNA和还原特征性DM1分子缺陷，包括RNA灶的错剪和积累。值得注意的是，与序列匹配的LNA gapmer相比，本研究中测试的BNA ^NC gapmers不诱导胱天蛋白酶激活。这项研究表明，BNA ^NC缺口聚体作为有前途的RNA靶向治疗剂值得进一步研究。