Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

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, w...

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Detalles Bibliográficos
Autores: García López, 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 Pló, Ignacio, Fournet, Guy, Orozco López, Modesto, Artero, Ruben, Metzger, Friedrich, Ebeling, Martin, Goekjian, Peter, Joseph, Benoît, Schwalbe, Harald, Scapozza, Leonardo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/122780
Acceso en línea:https://hdl.handle.net/2445/122780
Access Level:acceso abierto
Palabra clave:Cribratge
Atròfia muscular
Medical screening
Muscular atrophy
Descripción
Sumario: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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