RECTAS is a small molecule splice modulator that corrects aberrant splicing of familial dysautonomia (FD), promotes exon 20 inclusion of IKBKAP pre-mRNA and expression of IKAP.
RECTAS (2 uM) had an effect equivalent to kinetin at 50 uM in HeLa cells expressing the IKBKAP-FD reporter.
RECTAS promoted Exon 20 inclusion of endogenous IKBKAP pre-mRNA and increased IKAP expression in cells of patients with FD.
RECTAS at 2 uM recovered the level of IKAP to levels of IKAP in the cell line from the FD carrier.
RECTAS specifically restores the inclusion of weak exons whose recognition is suppressed by hnRNP H1/H2.
Familial dysautonomia (FD) is caused by missplicing of the IκB kinase complex-associated protein (IKAP) gene, which results in the skipping of exon 20, especially in neurons.
RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation.
RECTAS restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids.