Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model

• DOI: 10.1073/pnas.1901484116
• Publication Date: 2019-03-30T00:15:48Z
• Authors: Alicia J. Angelbello; Suzanne G. Rzuczek; Kendra K. Mckee; Jonathan L. Chen; Hailey Olafson; Michael D. Cameron; Walter N. Moss; Eric T. Wang; Matthew D. Disney
• Keywords: 0301 basic medicine; RNA Splicing; Oligonucleotides; Biological Sciences; 3. Good health; Bleomycin; Disease Models, Animal; Mice; 03 medical and health sciences; Drug Design; Animals; Humans; Myotonic Dystrophy; RNA; Trinucleotide Repeat Expansion

Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG) exp . The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG) exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG) exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.