GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330903/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330903GEOGSEfalseDepleting prion protein using splice-switching small moleculesPrion diseases are fatal neurodegenerative disorders driven by prion protein (PrP) misfolding, and lowering cellular PrP represents a promising therapeutic strategy. Here we report a small-molecule approach that reduces PrP by modulating pre-mRNA splicing of the PRNP gene. Through chemical modification of the clinically approved splicing modulator risdiplam, we generated CP3, the first class of compounds that selectively activate a cryptic exon in PRNP and routes its mRNA product for degradation, reducing PrP by ~70% in cells. We demonstrate that CP3 activity critically depends on alternative splicing factor Luc7L, revealing a novel requirement for alternative splicing factors in small molecule splicing modulation. Strikingly, co-administration of CP3 with a Luc7L activator PTC258 significantly lowers PrP levels in the brains of transgenic mice. These results establish splicing modulation as a powerful strategy for PrP reduction and highlight the potential of small-molecule cooperativity for therapeutic RNA targeting.2026/07/09GSE330903GSM9735450GSM9735472GSM9735473GSM9735451GSM9735470GSM9735471GSM9735458GSM9735459GSM9735456GSM9735457GSM9735476GSM9735454GSM9735455GSM9735474GSM9735452GSM9735453GSM9735475GSM9735461GSM9735462GSM9735460GSM9735449GSM9735447GSM9735469GSM9735448GSM9735467GSM9735468GSM9735446GSM9735465GSM9735466GSM9735463GSM973546434295330903Homo sapiens[42395399]