1. Academic Validation
  2. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice

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.
James Palacino 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
Affiliations

Affiliations

  • 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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