BNA(NC) Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells

作者：Manning Kassie S; Rao Ashish N; Castro Miguel; Cooper Thomas A^*

来源：ACS Chemical Biology, 2017, 12(10): 2503-2509.

DOI：10.1021/acschembio.7b00416

Myotonic dystrophy type 1 (DM1) is a multi-systemic 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.

• 出版日期2017-10