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Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7799-7804. doi: 10.1073/pnas.1901484116. Epub 2019 Mar 29.

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

Author information

1
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.
2
Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610.
3
Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610.
4
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458.
5
The Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011-1079.
6
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; disney@scripps.edu.

Abstract

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.

KEYWORDS:

RNA; RNA splicing; chemical biology; genetic disease; nucleic acids

Conflict of interest statement

Conflict of interest statement: M.D.D. and E.T.W. are consultants for Expansion Therapeutics. S.G.R. is a current employee of Expansion Therapeutics.

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