| First Author | Palacino J | Year | 2015 |
| Journal | Nat Chem Biol | Volume | 11 |
| Issue | 7 | Pages | 511-7 |
| PubMed ID | 26030728 | Mgi Jnum | J:355116 |
| Mgi Id | MGI:7737773 | Doi | 10.1038/nchembio.1837 |
| Citation | Palacino J, et al. (2015) SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol 11(7):511-7 |
| abstractText | 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. |
