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 towidespread spliceopathy and multisystemic disease manifestations. In addition to toxic RNA-mediated MBNLsequestration, dysregulation of specific microNAs further contributes to DM1 pathogenesis. In particular, miR-23bnegatively regulates MBNL1 expression, while anti-miR-23b therapeutic strategies have demonstrated restoration of MBNLactivity and improvement of DM1-associated phenotypes in preclinical models. Antisense oligonucleotide (ASO)-basedtherapeutic strategies are currently under development for DM1, including RNase H-mediated degradation of toxic DMPKtranscripts, steric-blocking approaches and modulation of pathogenic RNA-protein interactions. Multiple ASO-basedtherapeutic strategies targeting toxic DMPK RNA are currently advancing through preclinical and clinical development (seePoster 84: "Therapeutic Innovation, Clinical Trial Acceleration, and Lifestyle Interventions in Myotonic Dystrophy Type 1: ASystematic Review"). Despite promising therapeutic potential, productive intracellular delivery remains a major limitationfor oligonucleotide therapeutics. Following endocytic uptake, most ASOs remain trapped within endosomalcompartments, severely limiting productive nuclear delivery and therapeutic efficacy. Current approaches to enhanceendosomal escape include membrane-disrupting arents. lipid-based carriers. cell-penetrating peptides and modulation ofintracellular trafficking pathways?