# name
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

# metadata.dc.description.abstract[].value
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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Nature Communications, 2018, vol. 9, num. 2032

# metadata.dc.source[].value
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

# metadata.dc.title[].value
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes