DM1 treatment: a new turning point with genome and RNA technologies
An invisible enemy threatening muscle and cells
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, presenting with muscle weakness, myotonia, cardiac conduction abnormalities, and other diverse symptoms. The root cause is an unstable CTG repeat inserted in the 3' untranslated region of the DMPK gene; the resulting long CUG RNA sequesters RNA‑binding proteins, disrupting transcript splicing. This complex mechanism has posed a major challenge, as existing therapies cannot achieve fundamental improvement.
CRISPR and antisense take the stage
Recent studies have employed CRISPR‑based genome editing to directly delete or modify the expanded repeat, thereby blocking production of toxic RNA. Simultaneously, technologies that conjugate antisense oligonucleotides with cell‑penetrating peptides for efficient delivery to skeletal and cardiac muscle have advanced rapidly. These two approaches provide a direct route to suppress toxic transcripts while restoring normal splicing.
A new horizon for therapy
Gene‑editing and RNA‑silencing strategies are now entering clinical‑trial phases, increasing the likelihood of application to patients. If successful, DM1 patients could be liberated from muscle weakness and cardiac complications, resulting in a substantial improvement in quality of life.
Myotonic dystrophy type 1 is the most prevalent adult-onset muscular dystrophy and is characterized by progressive muscle weakness, myotonia, cardiac conduction defects, endocrine dysfunction, and central nervous system involvement. Myotonic dystrophy type 1 is caused by an unstable CTG repeat expansion in the 3' untranslated region of the DMPK gene, which produces toxic CUG-expanded transcripts that sequester RNA-binding proteins such as Muscleblind-like, induce widespread alternative splicing defects, and drive an RNA gain-of-function mechanism rather than simple DMPK haploinsufficiency. Despite major advances in understanding the molecular pathogenesis of myotonic dystrophy type 1, there is still no approved cure or disease-modifying therapy. This review summarizes the molecular basis of myotonic dystrophy type 1 and provides an in-depth overview of emerging therapeutic strategies that directly target the underlying pathogenic cascade at the DNA and RNA levels. Gene therapy-based approaches, including CRISPR-mediated genome editing, aim to reduce or eliminate the expanded CTG repeats or expanded DMPK allele and its toxic transcripts. In parallel, a broad spectrum of RNA-directed interventions is being developed, encompassing antisense oligonucleotides, antibody-penetrating and cell-penetrating peptide-conjugated antisense oligonucleotides to enhance skeletal and cardiac muscle delivery, small interfering RNAs, and microRNA-based tools such as antagomiRs. Additional strategies exploit engineered RNA-binding proteins and peptide decoys to disrupt toxic ribonuclear aggregates, polyadenylation signal-driven premature transcriptional termination to selectively silence mutant DMPK, and small molecules that modulate RNA metabolism, dissolve CUG RNA foci, or correct downstream mis-splicing. By integrating data from preclinical models and ongoing clinical trials, including recent advances with muscle‑targeted antisense oligonucleotide conjugates and gene therapy, this rev
The progressive muscle weakness and cardiac problems experienced by DM1 patients cannot be fundamentally halted with current therapies. Realization of novel gene‑ and RNA‑based treatments would enable patients to maintain mobility and cardiac health in daily life.