TREX1 mislocalization enables precision PROTAC therapy for a genetic disease

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE342342 | GEO | 2026/09/21

REPOSITORIES: GEO