SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice

Nat Chem Biol. 2015 Jul;11(7):511-7. doi: 10.1038/nchembio.1837. Epub 2015 Jun 1.


Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / metabolism
  • Muscular Atrophy, Spinal / mortality
  • Muscular Atrophy, Spinal / pathology
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Proteolysis
  • RNA Precursors / agonists
  • RNA Precursors / chemistry
  • RNA Precursors / metabolism
  • RNA, Double-Stranded / agonists*
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / metabolism
  • Ribonucleoprotein, U1 Small Nuclear / agonists*
  • Ribonucleoprotein, U1 Small Nuclear / chemistry
  • Ribonucleoprotein, U1 Small Nuclear / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Survival Analysis
  • Survival of Motor Neuron 2 Protein / chemistry
  • Survival of Motor Neuron 2 Protein / genetics
  • Survival of Motor Neuron 2 Protein / metabolism*


  • RNA Precursors
  • RNA, Double-Stranded
  • Ribonucleoprotein, U1 Small Nuclear
  • SMN2 protein, mouse
  • Small Molecule Libraries
  • Snrnp70 protein, mouse
  • Survival of Motor Neuron 2 Protein

Associated data

  • PubChem-Substance/250230386
  • PubChem-Substance/250230387
  • PubChem-Substance/250230388
  • PubChem-Substance/250230389