A Selective Alkylating Agent for CTG Repeats in Myotonic DystrophyType 1

Disease intervention at the DNA level generally hasbeen avoided because of off-target effects. Recent advances ingenome editing technologies using CRISPR-Cas9 have opened anew era in DNA-targeted therapeutic approaches. However,delivery of such systems remains a major challenge. Here, wereport a selective DNA-modifying small molecule that targets adisease-specific structure and mismatches involved in myotonicdystrophy type 1 (DM1). This ligand alkylates T-T mismatch-containing hairpins formedin the expanded CTG repeats(d(CTG)exp) in DM1. Ligand alkylation of d(CTG)expinhibitsthe transcription of d(CAGmiddotCTG)exp, thereby reducing the level ofthe toxic r(CUG)exptranscript. The bioactivity of the ligand also included a reduction in DM1 pathological features such as diseasefoci formation and misregulation of pre-mRNA splicing in DM1 model cells. Furthermore, the CTG-alkylating ligand may changethe d(CAGmiddotCTG)exprepeat length dynamics in DM1 patient cells. Our strategy of linking an alkylating moiety to a DNA mismatch-selective small molecule may be generally applicable to other repeat expansion diseases such as Huntington's disease andamyotrophic lateral sclerosis

Automated summary

A selective DNA-modifying small molecule has been developed that targets disease-specific structures and mismatches involved in myotonic dystrophy type 1 (DM1). This molecule has shown to inhibit the synthesis of toxic transcripts and improve disease features in DM1 model cells. The strategy used may be applicable for the treatment of other repeat expansion diseases.