Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

TitleTargeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
Publication TypeJournal Article
Year of Publication2018
AuthorsGarcia-Lopez, Amparo, Tessaro Francesca, Jonker Hendrik R. A., Wacker Anna, Richter Christian, Comte Arnaud, Berntenis Nikolaos, Schmucki Roland, Hatje Klas, Petermann Olivier, Chiriano Gianpaolo, Perozzo Remo, Sciarra Daniel, Konieczny Piotr, Faustino Ignacio, Fournet Guy, Orozco Modesto, Artero Ruben, Metzger Friedrich, Ebeling Martin, Goekjian Peter, Joseph Benoît, Schwalbe Harald, and Scapozza Leonardo
Date Published2018/05/23
ISBN Number2041-1723

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.

Short TitleNature Communications