Ali et al. 2025, efavirenz extends survival in a human-prion mouse model (JCI Insight)

A preclinical paper from the Calgary group of Sabine Gilch and Hermann Schatzl. It reports that very low oral doses of the HIV drug efavirenz, started 30 or 130 days after infection, lengthened survival by 17 and 23 days in mice expressing human prion protein and infected with sporadic CJD material, and that treatment shifted brain cholesterol handling. It is the most recent human-prion mouse study behind the registered efavirenz trial in Beijing.

Key facts

  • Title: "Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism". Authors Tahir Ali, Jessica Cashion, Samia Hannaoui, Hanaa Ahmed-Hassan, Hermann Schatzl and Sabine Gilch (corresponding), all at the University of Calgary. JCI Insight 2025;10(14):e190296, DOI 10.1172/jci.insight.190296, open access.
  • Model: female tg650 mice overexpressing human PrP (129MM), inoculated into the brain with 1% MM1 sporadic CJD brain homogenate at 6 to 8 weeks of age.
  • Treatment: efavirenz at 1.68 mg/L in drinking water, described as about 0.09 mg/kg/day, started at 30 or 130 days post inoculation and continued to terminal disease.
  • Survival: mean extension of 17 days (start at day 30) and 23 days (start at day 130) over untreated mice, with P below 0.001 by log-rank testing; groups were 9 untreated and 10 per treated arm.
  • At the early clinical stage (day 176) treated brains showed less proteinase K-resistant PrP, less cholesterol staining and lipid droplet marker, and less cleaved SREBF2, with more CYP46A1 and more 24S-hydroxycholesterol in brain and serum.
  • At the terminal stage PrPres did not differ between groups, and RT-QuIC seeding at day 176 did not differ, so the benefit is not simply a lower prion load throughout.
  • In infected N2a cells, overexpressing CYP46A1 lowered PrPres for two strains; the 24S-hydroxycholesterol rise was significant for one strain (22L) but not for the other (RML) in the reported panel statistics.
  • Funding came from the Alberta Prion Research Institute, a CIHR project grant (PJT-173385), Canada Research Chairs and fellowships; the authors declare no competing interests.
  • Timeline of the paper: received 18 December 2024, accepted 11 June 2025, published online 20 June 2025, issue dated 22 July 2025.
  • The Xuanwu trial registry record cites the authors' 2021 paper but not this one, so the link from this paper to the trial is the shared drug and group, not a stated citation.

Timeline

  1. 2024Manuscript received by JCI Insight (18 December).
  2. 2025Accepted (11 June) and published online (20 June).
  3. 2025Issue 10(14) dated 22 July.
  4. 2026Phase 3 efavirenz trial in sporadic and genetic CJD starts at Xuanwu Hospital, Beijing.

Last checked 1 November 2026

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