{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330903/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330903"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Depleting prion protein using splice-switching small molecules","description":"Prion 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.","dates":{"publication":"2026/07/09"},"accession":"GSE330903","cross_references":{"GSM":["GSM9735450","GSM9735472","GSM9735473","GSM9735451","GSM9735470","GSM9735471","GSM9735458","GSM9735459","GSM9735456","GSM9735457","GSM9735476","GSM9735454","GSM9735455","GSM9735474","GSM9735452","GSM9735453","GSM9735475","GSM9735461","GSM9735462","GSM9735460","GSM9735449","GSM9735447","GSM9735469","GSM9735448","GSM9735467","GSM9735468","GSM9735446","GSM9735465","GSM9735466","GSM9735463","GSM9735464"],"GPL":["34295"],"GSE":["330903"],"taxon":["Homo sapiens"],"PMID":["[42395399]"]}}