Small molecule selectively cleaves RNA that causes myotonic dystrophy type 1

In the neuromuscular disease myotonic dystrophy type 1 (DM1), a mutation causes RNA in cells to fold into a toxic structure. At the ACS national meeting, researchers at Scripps Research in Florida reported a small molecule that can selectively chop up this disease-causing RNA and rescue muscle function in mice with DM1-like symptoms. The DM1 mutation adds extra CTG repeats to the DMPK gene. The resulting long stretches of CUG repeats in RNA cause it to fold into a structure that starts binding important RNA-processing proteins in cells, leading to less expression of a critical ion channel for skeletal-muscle function. In previous work, Scripps’s Matthew D. Disney and colleagues designed a molecule that binds to the CUG-repeat structure. The new molecule, called cugamycin, consists of two of these binding molecules (shown, purple circles) connected to a modified version of the natural product bleomycin (yellow), which can cleave RNA. In mice with a DM1-like condition, cugamycin selectively cleaved CUG-repeat-containing RNAs, eliminating 97% of RNA-processing defects caused by the toxic RNAs, Disney said. Also, in normal mice, the molecule didn’t cleave off-target RNAs (Proc. Natl. Acad. Sci. U.S.A. 2019, DOI: 10.1073/pnas.1901484116). Disney said that the data demonstrate that chemists can develop small molecules that selectively target disease-causing RNAs.