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

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

Author information

1
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
2
Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.

Abstract

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.

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PMID:
26030728
DOI:
10.1038/nchembio.1837
[Indexed for MEDLINE]
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