2. Academic Validation
  3. Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

  • Nat Commun. 2018 May 23;9(1):2032. doi: 10.1038/s41467-018-04110-1.
Amparo Garcia-Lopez 1,  Francesca Tessaro 2,  Hendrik R A Jonker 3,  Anna Wacker 3,  Christian Richter 3,  Arnaud Comte 4,  Nikolaos Berntenis 5,  Roland Schmucki 5,  Klas Hatje 5,  Olivier Petermann 2,  Gianpaolo Chiriano 2,  Remo Perozzo 2,  Daniel Sciarra 2,  Piotr Konieczny 6 7,  Ignacio Faustino 8,  Guy Fournet 4,  Modesto Orozco 8,  Ruben Artero 6 7,  Friedrich Metzger 5,  Martin Ebeling 5,  Peter Goekjian 4,  Benoît Joseph 4,  Harald Schwalbe 3,  Leonardo Scapozza 9
Affiliations

Affiliations

  • 1 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. [email protected].
  • 2 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland.
  • 3 Institut für Organische Chemie und Chemische Biologie, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 7, 60438, Frankfurt, Germany.
  • 4 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69622, Villeurbanne cedex, France.
  • 5 Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 6 Translational Genomics Group, Incliva Health Research Institute, Menendez Pelayo 4, 46010, Valencia, Spain.
  • 7 Department of Genetics and Interdisciplinary Research Structure for Biotechnology and Biomedicine (ERI BIOTECMED), University of Valencia, Dr Moliner 50, 46100, Burjassot, Spain.
  • 8 Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology (BIST), Joint BSC-IRB Research Program in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain.
  • 9 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. [email protected].
PMID: 29795225 DOI: 10.1038/s41467-018-04110-1
Abstract

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5' splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.

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