Enhancing Antisense Oligonucleotide Activity in Myotonic Dystrophy Type 1 by Genetic and Chemical Modulation

Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder caused by expanded CT repeats in the DMPK gene.
Mutant DMPK transcripts accumulate as nuclear RNA foci and sequester Muscleblind-like (MBNL) proteins, leading to
widespread spliceopathy and multisystemic disease manifestations. In addition to toxic RNA-mediated MBNL
sequestration, dysregulation of specific microNAs further contributes to DM1 pathogenesis. In particular, miR-23b
negatively regulates MBNL1 expression, while anti-miR-23b therapeutic strategies have demonstrated restoration of MBNL
activity and improvement of DM1-associated phenotypes in preclinical models. Antisense oligonucleotide (ASO)-based
therapeutic strategies are currently under development for DM1, including RNase H-mediated degradation of toxic DMPK
transcripts, steric-blocking approaches and modulation of pathogenic RNA-protein interactions. Multiple ASO-based
therapeutic strategies targeting toxic DMPK RNA are currently advancing through preclinical and clinical development (see
Poster 84: "Therapeutic Innovation, Clinical Trial Acceleration, and Lifestyle Interventions in Myotonic Dystrophy Type 1: A
Systematic Review"). Despite promising therapeutic potential, productive intracellular delivery remains a major limitation
for oligonucleotide therapeutics. Following endocytic uptake, most ASOs remain trapped within endosomal
compartments, severely limiting productive nuclear delivery and therapeutic efficacy. Current approaches to enhance
endosomal escape include membrane-disrupting arents. lipid-based carriers. cell-penetrating peptides and modulation of
intracellular trafficking pathways?