Furamidine and heptamidine rescue myotonic dystrophy type I associated mis-splicing: Mus musculus raw sequence reads

Myotonic dystrophy type 1 (DM1) is an autosomal dominant, CTG microsatellite expansion disease. Transcription of the CTG repeats gives rise to CUG repeat RNA with a toxic gain-of-function. The toxic CUG RNA sequesters the muscleblind-like (MBNL) family of RNA-binding proteins and disrupts their normal cellular function causing global mis-regulation of RNA processing. Multiple approaches have been developed to target the toxic RNA; these include, but are not limited to, displacing MBNL proteins from the CUG repeats, increasing MBNL protein levels or delivery of exogenous MBNL proteins, and blocking the transcription of the CUG repeats. From a screen of diamidine molecules, we previously identified furamidine as a promising lead molecule that was shown to reduce ribonuclear foci and rescue mis-splicing of splicing reporters in a HeLa cell model of DM1. We reported that treatment of the HSALR DM1 mouse model with furamidine partially rescued the Atp2a1 and Clcn1 mis-splicing events via RT-PCR. Here, using RNA-seq examine global splicing, we report that furamidine rescued over 70 mis-splicing events in the HSALR DM1 mouse model and minimally affected gene expression. Heptamidine, in comparison, rescued ~62 events but caused significant alterations in gene expression.

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