Identification of enzymatically modified isoquercitrin as a therapeutic lead for myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a complex multisystemic disease caused by a CTG repeat expansion in the DMPK gene for which there are no approved disease-modifying treatments. Transcription of the expanded allele produces toxic gain-of-function CUG-expansion RNA that sequesters the MBNL family of alternative splicing regulators into ribonuclear foci, leading to pathogenic mis-splicing. In this study, using our previously established HeLa DM1 repeat selective screening platform, we identified the natural flavonoid quercetin as a selective modulator of toxic CUG RNA levels. Quercetin treatment selectively reduced DMPK levels and rescued MBNL-dependent mis-splicing in DM1 patient-derived myotubes. To overcome the limited bioavailability of quercetin in vivo, we evaluated a bioavailable derivative of quercetin, enzymatically modified isoquercitrin (EMIQ), in the HSA ^LR DM1 skeletal muscle mouse model. EMIQ treatment of these mice through the drinking water selectively reduced the expanded CUG transcripts and rescued mis-splicing and myotonia. Given its efficacy in the HSA ^LR mouse model and the established safety profile in humans, we have identified EMIQ as a priority disease-targeting therapeutic lead for future clinical evaluation in DM1.