biostudies-literatureVallabh SMHHS | National Institutes of HealthNINDS NIH HHSe0167222https://www.ebi.ac.uk/biostudies/studies/S-EPMC9973041biostudies-literatureUnknown97(2)Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective <i>in vivo</i> against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were oJournal of virologyTherapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.PMC9973041P01 NS041997R01 NS125255Kriz JPitstick RO'Moore JCabin DECarlson GAMinikel EVVallabh SMJackson WSPeters JZou DSilvius DfalseTherapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective <i>in vivo</i> against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were o2023-01-01T00:00:00Z2023 Feb2025-04-19T02:44:44.813Z2025-02-19T04:54:46.728ZS-EPMC99730413665174810.1128/jvi.01672-22