1 research outputs found
BNA<sup>NC</sup> Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells
Myotonic dystrophy type 1 (DM1) is
a multisystemic disease caused by an expanded CTG repeat in the 3′
UTR of the <i>dystrophia myotonica protein kinase</i> (<i>DMPK</i>) gene. Short, DNA-based antisense oligonucleotides
termed gapmers are a promising strategy to degrade toxic CUG expanded
repeat (CUG<sub>exp</sub>) 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<sup>NC</sup>[NMe] (BNA<sup>NC</sup>) modification is a promising nucleoside
analog with high potency similar to 2′,4′-LNA (LNA).
BNA<sup>NC</sup> gapmers targeting a nonrepetitive region of the DMPK
3′ UTR show allele-specific knockdown of CUG<sub>exp</sub> RNA
and revert characteristic DM1 molecular defects including mis-splicing
and accumulation of RNA foci. Notably, the BNA<sup>NC</sup> gapmers
tested in this study did not induce caspase activation, in contrast
to a sequence matched LNA gapmer. This study indicates that BNA<sup>NC</sup> gapmers warrant further study as a promising RNA targeting
therapeutic