{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342342/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342342"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"TREX1 mislocalization enables precision PROTAC therapy for a genetic disease","description":"Proteolysis-targeting chimeras (PROTACs) have been developed primarily for cancer, and their application to genetic disease remains largely unexplored. Unlike gene editing, which requires a bespoke intervention for each patient's mutation, a protein degrader could address many mutations at once, provided they share a common, druggable feature. We asked whether protein mislocalization could serve as that feature. We tested this in retinal vasculopathy with cerebral leukoencephalopathy (RVCL), a universally fatal condition caused by gain-of-function mutations in three-prime repair exonuclease-1 (TREX1), a key negative regulator of cGAS- and STING-mediated interferon (IFN) responses. Many different mislocalized TREX1 mutants cause RVCL, producing the same multi-organ disease. Here we show that a single PROTAC eliminates all known RVCL-causing variants while sparing membrane anchored wild-type TREX1. Selectivity is associated with loss of membrane anchoring, which renders the mutant accessible to degradation, thereby preventing death in a model of RVCL while preserving the essential activity of WT TREX1. Thus, a single small molecule targets diverse mislocalized mutants, establishing altered protein localization as a druggable path for PROTAC therapy.","dates":{"publication":"2026/09/21"},"accession":"GSE342342","cross_references":{"GSM":["GSM9928794","GSM9928793","GSM9928792","GSM9928791","GSM9928798","GSM9928797","GSM9928796","GSM9928795","GSM9928800","GSM9928789","GSM9928799","GSM9928790"],"GPL":["34328"],"GSE":["342342"],"taxon":["Mus musculus"]}}