Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease whose pathogenesis stems from the functional loss of muscleblind-like RNA-binding proteins (RBPs), which causes the formation of alternative-splicing defects. The loss of functional muscleblind-like protein 1 (MBNL1) results from its nuclear sequestration by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp). Here we show that an MBNL1? RBP engineered to act as a decoy for CUGexp reverses the toxicity of the mutant transcripts. Overall design: In thIs study, Gastrocnemius muscles of WT mice were injected with either saline, AAV-GFP or AAV-GFP-MBNL1?, and overall transcriptome changes were analyzed by RNAseq.