molecules of the month

An oral, brain-penetrant splicing modulator targeting ELP1. Incorrect splicing of the Elongator complex protein 1 (ELP1) gene causes Familial Dysautonomia (FD), a neurodegenerative disease that results in uncoordinated movement, blindness through retinal degeneration, and risk of unexplained sudden death, among other symptoms. A single T-to-C nucleotide change in the 5’ splice site of ELP1 intron 20 leads to skipping of ELP1 exon 20 and a reduction in ELP1 protein in the CNS and PNS. There are no effective treatments for FD, though antisense oligonucleotides, modified exon-specific U1 small nuclear RNAs, and splicing modulator compounds have been investigated. PTC258 is an oral, brain-penetrant small molecule that increases functional ELP1 protein levels in the CNS by correcting splicing of mutant ELP1 pre-mRNA.…