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

doi: 10.1038/nchembio.1837. Epub 2015 Jun 1.

Susanne E Swalley  1 , Cheng Song  1 , Atwood K Cheung  1 , Lei Shu  1 , Xiaolu Zhang  1 , Mailin Van Hoosear  1 , Youngah Shin  1 , Donovan N Chin  1 , Caroline Gubser Keller  2 , Martin Beibel  2 , Nicole A Renaud  1 , Thomas M Smith  1 , Michael Salcius  1 , Xiaoying Shi  1 , Marc Hild  1 , Rebecca Servais  1 , Monish Jain  1 , Lin Deng  1 , Caroline Bullock  1 , Michael McLellan  1 , Sven Schuierer  2 , Leo Murphy  1 , Marcel J J Blommers  2 , Cecile Blaustein  1 , Frada Berenshteyn  1 , Arnaud Lacoste  1 , Jason R Thomas  1 , Guglielmo Roma  2 , Gregory A Michaud  1 , Brian S Tseng  1 , Jeffery A Porter  1 , Vic E Myer  1 , John A Tallarico  1 , Lawrence G Hamann  1 , Daniel Curtis  1 , Mark C Fishman  1 , William F Dietrich  1 , Natalie A Dales  1 , Rajeev Sivasankaran  1

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

James Palacino et al. Nat Chem Biol. 2015 Jul.

Erratum in

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

    Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R. Palacino J, et al. Nat Chem Biol. 2015 Sep;11(9):741. doi: 10.1038/nchembio0915-741a. Nat Chem Biol. 2015. PMID: 26284678 No abstract available.

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

    Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R. Palacino J, et al. Nat Chem Biol. 2016 Apr;12(4):304. doi: 10.1038/nchembio0416-304c. Nat Chem Biol. 2016. PMID: 26991088 No abstract available.

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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