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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.

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


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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