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

Abstract 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 HSALR 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 HSALR 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.