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.

Products