Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Amparo Garcia-Lopez (), Francesca Tessaro, Hendrik R. A. Jonker, Anna Wacker, Christian Richter, Arnaud Comte, Nikolaos Berntenis, Roland Schmucki, Klas Hatje, Olivier Petermann, Gianpaolo Chiriano, Remo Perozzo, Daniel Sciarra, Piotr Konieczny, Ignacio Faustino, Guy Fournet, Modesto Orozco, Ruben Artero, Friedrich Metzger, Martin Ebeling, Peter Goekjian, Benoît Joseph, Harald Schwalbe and Leonardo Scapozza ()
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Amparo Garcia-Lopez: University of Lausanne and University of Geneva
Francesca Tessaro: University of Lausanne and University of Geneva
Hendrik R. A. Jonker: Johann Wolfgang Goethe-University Frankfurt
Anna Wacker: Johann Wolfgang Goethe-University Frankfurt
Christian Richter: Johann Wolfgang Goethe-University Frankfurt
Arnaud Comte: University Claude Bernard Lyon 1
Nikolaos Berntenis: F. Hoffmann-La Roche
Roland Schmucki: F. Hoffmann-La Roche
Klas Hatje: F. Hoffmann-La Roche
Olivier Petermann: University of Lausanne and University of Geneva
Gianpaolo Chiriano: University of Lausanne and University of Geneva
Remo Perozzo: University of Lausanne and University of Geneva
Daniel Sciarra: University of Lausanne and University of Geneva
Piotr Konieczny: Incliva Health Research Institute
Ignacio Faustino: Joint BSC-IRB Research Program in Computational Biology
Guy Fournet: University Claude Bernard Lyon 1
Modesto Orozco: Joint BSC-IRB Research Program in Computational Biology
Ruben Artero: Incliva Health Research Institute
Friedrich Metzger: F. Hoffmann-La Roche
Martin Ebeling: F. Hoffmann-La Roche
Peter Goekjian: University Claude Bernard Lyon 1
Benoît Joseph: University Claude Bernard Lyon 1
Harald Schwalbe: Johann Wolfgang Goethe-University Frankfurt
Leonardo Scapozza: University of Lausanne and University of Geneva

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04110-1

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DOI: 10.1038/s41467-018-04110-1

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