Myotonin-protein kinase (DMPK) messenger RNA with expanded CUG repeats (DMPK mRNA (CUG)n)

Myotonin-protein kinase (DMPK) messenger RNA with expanded CUG repeats is the central pathogenic agent in Myotonic Dystrophy Type 1 (DM1), a multisystemic neuromuscular disorder (Thornton, 2014, PubMed). The expansion of CTG repeats in the 3' untranslated region of the DMPK gene results in the production of mutant mRNA containing long CUG tracts that fold into stable hairpin structures (Mankodi et al., 2000, Science). These toxic transcripts accumulate in the nucleus as discrete foci, where they sequester RNA-binding proteins, most notably the Muscleblind-like (MBNL) family (Miller et al., 2000, EMBO J). The loss of MBNL function leads to widespread alternative splicing defects in downstream genes such as CLCN1 and INSR, causing myotonia and insulin resistance (Kanadia et al., 2003, Science). Therapeutic strategies focus on reducing the burden of this toxic RNA using antisense oligonucleotides (ASOs) or siRNA to trigger its degradation (Wheeler et al., 2012, Nature). Current clinical candidates like delpacibart etedesiran (AOC 1001) and DYNE-101 utilize these mechanisms to restore splicing homeostasis and improve muscle function (Avidity Biosciences, 2023; Dyne Therapeutics, 2024). Successful targeting requires efficient delivery to skeletal, cardiac, and smooth muscle tissues to address the systemic nature of the disease. Monitoring efficacy often involves measuring the splicing index, a composite score of multiple MBNL-dependent splicing events in muscle biopsies.

Other names

DMPK mRNA with expanded CUG repeatsToxic DMPK mRNACUG expansion RNADM1 mRNADystrophia myotonica protein kinase mRNA

Degradation of the expanded DMPK mRNA via RNase H-mediated cleavage (ASOs) or RNA interference (siRNA), or disruption of RNA-protein interactions to release sequestered splicing factors.