BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells
journal contributionposted on 30.08.2017, 00:00 by Kassie S. Manning, Ashish N. Rao, Miguel Castro, Thomas A. Cooper
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.
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increase gapmer affinitydystrophia myotonica protein kinaseDMPKBNA NC Gapmers Revert SplicingBNA NC gapmers warrantLNA gapmerCUG exp RNAexhibit toxicityBNA NC gapmerscaspase activationDNA-based antisense oligonucleotidesnucleoside analognonrepetitive regionCUG expLow ToxicityCTGRNA fociDM 1Myotonic Dystrophy Cells Myotonic dystrophy type 1multisystemic diseaseNucleoside analogsRNA FociUTRBNA NC