Myotonic dystrophy (DM) types 1 (DM1) and 2 (DM2) are caused by autosomal dominant gain-of-function RNA which are, in turn, created by the expansion of repeat sequences in the DMPK and ZNF9 genes, respectively. The expansions are highly unstable and biased for further expansion in somatic cells and across generations. Despite the different genes involved, DM1 and DM2 share several clinical features due to having the similar underlying mechanism of repetitive RNA-mediated toxicity. Both disorders manifest as multisystemic conditions with features including myotonia, cataract development, and abnormalities in cardiac conduction. At present, there is no cure for DM and treatments mostly aim at symptom management. Among the therapeutics being developed, antisense therapy using gapmers is one of the most promising. Compared to other antisense oligonucleotides, gapmers maintain the ability to induce RNase H cleavage while having enhanced target binding affinity and nuclease resistance. This chapter will consolidate the different strategies studied thus far to develop a treatment for DM1 through the targeting of toxic repetitive RNA using gapmers.
Keywords: CUG-binding protein 1 (CUGBP1); Cardiac troponin T (TNNT3); ClC-1; DMPK; IONIS (ISIS)-DMPKRx (IONIS-DMPK-2.5Rx); Insulin receptor (IR); Locked nucleic acid (LNA); Muscleblind-like (MBNL) family; Toxic RNA; ZNF9.