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
  • 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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