Erratum: Corrigendum: SMN2 splice modulators enhance U1–pre-mRNA association and rescue SMA mice

Abstract

In the version of this caption initially published, the cover artwork was credited to Erin Dewalt, based on imagery from the author, rather than stating that it was created by Michael B. Battles and the design was by Erin Dewalt. The error has been corrected in the HTML and PDF versions of the caption. ERRATUMIn the version of this article originally published online, the schematic for the construct in Figure 4a was incorrect. A corrected figure has been provided in the HTML and PDF versions of the article.

Targeting RNA structures with small molecules

“…Assays completed in mammalian cells typically use generation of either luciferase or a fluorescent protein as a readout. Two small molecules that modulate splicing were discovered from phenotypic screens, the FDA-approved risdiplam 66 and branaplam 15 (currently in phase II clinical trials) for the treatment of spinal muscular atrophy (SMA) 15 .…”

“…The small molecule branaplam was also identified from a similar phenotypic screen of SMN2 exon 7 alternative splicing, using a mini-gene reporter of a breast cancer 1 (BRCA1) exon 18 mutant that induces exon skipping as a counter-screen 15 . A series of studies using a related molecule, NVS-SM2, pinpointed that the molecule interacted with 21 nucleotides of the SMN2 5′ splice site, in particular a GA sequence found at the end of exon 7, suggesting involvement of U1 snRNP.…”

“…A series of studies using a related molecule, NVS-SM2, pinpointed that the molecule interacted with 21 nucleotides of the SMN2 5′ splice site, in particular a GA sequence found at the end of exon 7, suggesting involvement of U1 snRNP. NVS-SM2 acts as a molecular glue, as U1 snRNP only bound to SMN2 exon 7 when the small molecule was present 15 . Branaplam was later discovered to reduce mutant huntingtin (mHTT) protein levels by facilitating pseudo-exon inclusion in the HTT mRNA 261 .…”

“…Several small molecules that bind RNA structures have been identified that exhibit various modes of action (MOAs), from simple binding to direct cleavage to recruitment of endogenous nucleases (induced proximity). These molecules have been demonstrated to modulate diverse biological processes, such as inhibiting bacterial and viral translation (ribocil and a riboswitch in Escherichia coli 11 , 2-aminobenzimidazole derivatives and the hepatitis C internal ribosome entry site (IRES) 12 ); inhibiting mRNA translation (synucleozid and α-synuclein 13 ); facilitating alternative pre-mRNA splicing (risdiplam 14 and branaplam 15 and survival of motor neuron 2 (SMN2)); and inhibiting microRNA (miRNA) biogenesis (a spermine–amidine conjugate and the miR-372 precursor 16 ).…”