Recent Advances in Therapeutic Strategies for Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder caused by expanded CTG repeats in the 3′ untranslated region of the DMPK gene, which produce toxic CUG-expanded RNA. This mutant RNA forms nuclear foci that sequester MBNL proteins and disrupt alternative splicing across numerous genes, leading to clinical manifestations involving skeletal muscle, the heart, respiratory function, endocrine systems, and the central nervous system. Current management is supportive and focuses on physical therapy, mexiletine for myotonia, cardiac surveillance, ventilatory assistance, and behavioral or cognitive interventions. Advances in molecular pathogenesis have accelerated the development of disease-modifying therapies aimed at the root cause. Four major therapeutic strategies are emerging: reduction of toxic DMPK transcripts via antisense oligonucleotides or siRNAs; restoration of MBNL function through steric-blocking oligonucleotides, peptide-conjugated modalities, or anti-miR approaches; modulation of dysregulated signaling pathways such as GSK3β; and gene- or genome-editing technologies, including AAV-mediated RNA interference and CRISPR/Cas9-based repeat excision. Several investigational agents-such as AOC 1001, DYNE-101, EDODM1, and ATX-01-have demonstrated promising molecular and early clinical improvements in phase 1/2 studies. These advances mark a significant transition from symptomatic care to precise molecular correction. As these therapeutic platforms continue to mature, DM1 may soon shift from a largely untreatable condition to a biologically modifiable disease with meaningful clinical impact.