5 years ago

BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells

BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells
Miguel Castro, Ashish N. Rao, Thomas A. Cooper, Kassie S. Manning
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 (CUGexp) 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′-BNANC[NMe] (BNANC) modification is a promising nucleoside analog with high potency similar to 2′,4′-LNA (LNA). BNANC gapmers targeting a nonrepetitive region of the DMPK 3′ UTR show allele-specific knockdown of CUGexp RNA and revert characteristic DM1 molecular defects including mis-splicing and accumulation of RNA foci. Notably, the BNANC gapmers tested in this study did not induce caspase activation, in contrast to a sequence matched LNA gapmer. This study indicates that BNANC gapmers warrant further study as a promising RNA targeting therapeutic.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00416

DOI: 10.1021/acschembio.7b00416

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