Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.

Prion diseases are fatal, infectious, and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent prion disease. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain-specific cholesterol-metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the antiprion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30 or 130 days postinfection significantly slowed disease progression and extended their survival. At early clinical stage, we observed reduced PrPSc accumulation, decreased cholesterol and lipid droplet content, and elevated CYP46A1 and 24S-HC levels in EFV-treated mice. Overexpression of CYP46A1 in prion-infected neuronal cells reduced PrPSc levels and increased 24S-HC, indicating that antiprion effects of EFV correlate with CYP46A1 activation. These findings highlight EFV as a safe and efficacious therapeutic candidate for human prion diseases.