Antisense Oligonucleotide-Mediated Degradation of Toxic RNA in Myotonic Dystrophy Type 1

Myotonic dystrophy (DM) exists in two forms, type 1 (DM1) and type 2 (DM2), both inherited in an autosomal dominant manner and caused by toxic gain-of-function RNAs produced from unstable repeat expansions. In DM1, the mutation lies in the DMPK gene, whereas in DM2 it involves the CNBP gene. These repeats are inherently unstable, with a strong tendency to further expand in somatic tissues and across generations, driving disease progression and anticipation. Despite arising from distinct genetic defects, DM1 and DM2 share a common pathogenic pathway-RNA-mediated toxicity-which accounts for their overlapping clinical manifestations. Both are multisystemic disorders characterized by myotonia, early cataracts, and defects in cardiac conduction, alongside a range of additional systemic complications. To date, no curative therapy is available, and management remains largely symptomatic. Among experimental approaches, antisense oligonucleotide (AON) therapies-particularly gapmers-have emerged as one of the most promising strategies. Gapmers are designed to resist nuclease degradation and bind their targets with high affinity while still promoting RNase H-mediated cleavage of toxic transcripts, making them especially suitable for targeting nuclear-retained repeat RNAs. This chapter summarizes current progress in the development of gapmer-based AONs for DM1, highlighting both their therapeutic potential and the challenges that must be overcome for successful clinical translation.