Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules.

Therapeutic Approaches


The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)(exp)). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)(exp) and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)(exp). This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)(exp) and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.


Childs-Disney, Jessica L; Stepniak-Konieczna, Ewa; Tran, Tuan; Yildirim, Ilyas; Park, HaJeung; Chen, Catherine; Hoskins, Jason; Southall, Noel; Marugan, Juan; Patnaik, Samarjit; Zheng, Wei; Austin, Christopher; Schatz, George C; Sobczak, Krzysztof; Thornton, Charles A; Disney, Matthew D;


  • Animals
  • Base Sequence
  • Exons/ genetics
  • Fibroblasts/ drug effects
  • Fibroblasts/ metabolism
  • Fibroblasts/ pathology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Myotonic Dystrophy/ drug therapy
  • Myotonic Dystrophy/ genetics
  • Plasmids/ metabolism
  • Protein Binding/ genetics
  • Protein Biosynthesis/ drug effects
  • RNA/ metabolism
  • RNA Precursors/ genetics
  • RNA Precursors/ metabolism
  • RNA Splicing/ drug effects
  • RNA Splicing/ genetics
  • RNA-Binding Proteins/ genetics
  • RNA-Binding Proteins/ metabolism
  • Receptor, Insulin/ genetics
  • Small Molecule Libraries/ chemistry
  • Small Molecule Libraries/ pharmacology
  • Small Molecule Libraries/ therapeutic use

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