RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease caused by abnormal transcripts containing expanded CUG repeats. The CUG transcripts aggregate in the nucleus to form RNA foci and lead to nuclear depletion of Muscleblind-like 1 (MBNL1) and stabilized expression of CUGBP Elav like family 1 (CELF1), both of which are splicing regulatory proteins. The imbalance of these proteins results in misregulation of alternative splicing and neuromuscular abnormalities. Here, we report the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in DM1. We designed chimeric ASOs, termed gapmers, containing modified nucleic acid residues to induce RNase H-mediated degradation of CUG-repeat transcripts. The gapmers selectively knockdown expanded CUG transcripts and are sufficient to disrupt RNA foci both in cell culture and mouse models for DM1. Furthermore, combination of gapmers with morpholino ASOs that help release binding of MBNL1 to the toxic RNA can potentially enhance the knockdown effect. Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy.