molecules of the month


oral ELP1 ex20 splicing modulator

rescues motor coordination in FD mouse model

opt. from natural product from 1K cmpd screen

bioRxiv, 04 November 2022

Mass General Research Institute / PTC Therapeutics

PTC258 chemical structure oral ELP1 ex20 splicing modulator- Mass General Research Institute / PTC Therapeutics
3 mins read

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.…

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