Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy.

ABSTRACT: Designing an RNA-interacting molecule that displays high therapeutic efficacy while retaining specificity within a broad concentration range remains a challenging task. Risdiplam is an FDA-approved small molecule for the treatment of spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. Branaplam is another small molecule which has undergone clinical trials. The therapeutic merit of both compounds is based on their ability to restore body-wide inclusion of Survival Motor Neuron 2 (SMN2) exon 7 upon oral administration. Here we compare the transcriptome-wide off-target effects of these compounds in SMA patient cells. We captured concentration-dependent compound-specific changes, including aberrant expression of genes associated with DNA replication, cell cycle, RNA m

SUBMITTER: Ottesen EW 

PROVIDER: S-EPMC10325915 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature