Selected Grantee Publications

Diverse Targets of SMN2-Directed Splicing-Modulating Small Molecule Therapeutics for Spinal Muscular Atrophy

Ottesen et al., Nucleic Acids Research. 2023.

https://academic.oup.com/nar/article/51/12/5948/7110763?login=true

Spinal muscular atrophy (SMA) results from deletions or mutations of the SMN1 gene. SMN2 is a nearly identical copy of SMN1 but cannot compensate for its loss. Manipulation of splicing to restore SMN2 exon 7 inclusion provides a promising therapeutic avenue for SMA, and two small-molecule agents—risdiplam and branaplam—restore body-wide inclusion of the SMN2 exon 7 upon oral administration. In this study, researchers demonstrate the advantages of combined treatments with low doses of risdiplam and branaplam. These findings can be applied to develop the next generation of small‑molecule therapeutics, with a focus on better efficacies and fewer off-target effects. Supported by ORIP (T35OD027967) and NINDS.