Antisense-mediated gene therapy targeting DMPK restores cardiac ion channel function and electrical stability in...

Myotonic dystrophy type 1 (DM1) is characterized by toxic RNA gain of function leading to cardiac conduction defects and life-threatening arrhythmias. Current therapeutic options remain limited.

We evaluated the molecular and electrophysiological efficacy of IONIS-486178, an antisense oligonucleotide (ASO) targeting mutant DMPK transcripts in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from a patient with DM1.

DM1 hiPSC-CMs were treated with IONIS-486178 for 24 hours. Efficacy was assessed using reverse transcription quantitative polymerase chain reaction for DMPK knockdown and splicing analysis, fluorescence in situ hybridization for nuclear foci quantification, western blot for ion channel protein expression, and whole-cell patch clamp for ionic currents and action potential characterization.

Treatment of hiPSC-CMs with IONIS-486178 (5 μmol/L) achieved ∼90% DMPK knockdown, reduced toxic nuclear foci, and corrected SCN5A mis-splicing toward the adult isoform. Functionally, IONIS-486178 fully restored all ionic currents (sodium, L-type calcium, and potassium currents) reduced in DM1 hiPSC-CMs. This electrophysiological rescue correlated with re-expression of the corresponding ion channel proteins. The treatment also normalized action potential kinetics and durations and significantly reduced the incidence of arrhythmogenic events.

ASO-mediated suppression of DMPK is sufficient to reverse core electrophysiological defects and reduce arrhythmogenic events in a human cellular model of DM1. These findings validate the biological rationale of targeting DMPK to prevent DM1-associated cardiac complications, supporting the continued development of next-generation ASO delivery platforms.