Development and Characterization of ASO-based Ribonuclease Targeting Chimera for the Degradation of CUG RNA Repeat Expansion in Myotonic Dystrophy Type

Myotonic Dystrophy Type 1 is a multisystemic genetic disorder that primarily affects the muscles in the body leading to such pathologies as myotonia, muscle atrophy, insulin resistance and even neurological deficits. This disorder is caused by a series of CUG repeats in the 3’ untranslated region of the DMPK gene; symptoms appear after around 34 repeats. These repeats form foci when MBNL1 protein that deals with alternative splicing of many events in the body, forms aggregations around these repeats. These foci render the MBNL 1 proteins useless. There is no FDA approved therapeutic, but many RNA targeting therapeutics have been explored as treatment. This paper focuses on a novel therapeutic method called ModRTAC. ModRTAC drew inspiration for the original RiboTAC design which uses RNAseL to degrade RNA targets. After treating a HeLa CTG 480 model meant to model DM1 with ModRTAC, there was a rescue of key splicing events and reduction of RNA foci. The positive results in this paper show a promising future for treatment of other satellite repeat diseases.