T.I.1 Targeted therapies for myotonic dystrophy

Abstract

Our current understanding of the disease process in myotonic dystrophy is still incomplete. Nevertheless, recent efforts to develop therapy have progressed rapidly, mainly by targeting the RNA that contains an expanded repeat. Expression of this repetitive RNA has many deleterious effects on the muscle transcriptome, such as, abnormalities of RNA splicing, localization, and decay. One of the more promising therapeutic strategies involves the use of RNase H-active antisense oligonucleotides (ASOs) to accelerate the clearance of toxic RNA. Studies in mouse models have shown that knocking down the level of toxic RNA can lead to overall improvement of the muscle transcriptome and elimination of the myotonia. Studies also suggest that expanded-CUG-repeat transcripts are unusually sensitive to antisense knockdown, suggesting an opportunity for allele-specific reduction of the mutant RNA. Another strategy that has shown beneficial effects in mouse models has been to block the interaction of CUG repeats with RNA binding proteins. This can be done either with antisense oligonucleotides or small-molecule drug-like compounds. This presentation will summarize the progress in developing targeting treatments for myotonic dystrophy, and efforts to become “trial ready” by identifying useful biomarkers and clinical endpoints for trials.