CYP46A1 activation (efavirenz) to alter brain cholesterol turnover in prion disease

Key facts

• Mechanism proposed: efavirenz activates CYP46A1, raising 24S-hydroxycholesterol and lowering activated SREBF2 (a cholesterol synthesis driver) and free cholesterol in treated mouse brain.
• Brain Cyp46A1 protein was lower in terminal mice infected with RML, 22L or ME7 prions and in post-mortem sporadic CJD brain (four per group), but unchanged at 75 to 125 days after infection.
• RML-infected C57BL/6J mice given 0.09 mg/kg/day in drinking water lived 11.4 days longer when treated from inoculation, 18.7 days from day 30 and 16.1 days from day 50, against 170.9 days for controls.
• In mice carrying human PrP and infected with MM1 sporadic CJD prions, treatment from 30 or 130 days after infection extended mean survival by 17 and 23 days (log-rank P below 0.001); the dose was roughly 300 to 400 times below the HIV dose by the authors' estimate.
• Early clinical stage treated brains had less PrPres, more 24S-hydroxycholesterol in brain and serum, and less free cholesterol.
• Null or weak results: terminal-stage PrPres and RT-QuIC seeding did not differ between groups, efavirenz did not raise CYP46A1 in reactive astrocytes, and the earliest start (day 0) gave a smaller gain than later starts in the RML study.
• Limits of the evidence: only female mice, one human-PrP strain in vivo, small biochemistry groups (n=5, n=3), and the causal claim leans on CYP46A1 overexpression in cell lines.
• Human target engagement exists outside prion disease: a 2022 pilot in five people with early Alzheimer's disease (50 or 200 mg daily for 20 weeks) saw plasma 24-hydroxycholesterol rise, with no serious adverse events, but it was too small for efficacy.
• Dose caution: mouse work cited in the Alzheimer's pilot reported that doses above about 0.22 mg/kg/day inhibited CYP46A1 while lower doses activated it; the human optimum is unknown.
• The Xuanwu phase 3 trial (NCT07482085) uses 200 mg then 400 mg at bedtime, 246 planned participants, median survival to 36 months as primary endpoint, no results posted.
• Cholesterol lowering as such has a poor record in prion models: a cell study states cholesterol depletion per se does not reduce PrPSc formation, and secondary reports describe statin mouse results as mixed.
• A gene-therapy route to CYP46A1 exists only outside prion disease: AAV-CYP46A1 corrected amyloid and tau pathology in Alzheimer's mouse models (French teams, 2015), with a stated intention to seek clinical trial authorisation. No prion application was found.

Timeline

1. 2015French teams report AAV-mediated CYP46A1 overexpression corrects amyloid pathology in mice (Brain, 3 July); tau paper follows in September.
2. 2018Case Western pilot of low-dose efavirenz in early Alzheimer's disease starts (NCT03706885).
3. 2021Calgary reports efavirenz prolongs survival of RML-infected mice and implicates Cyp46A1.
4. 2022Alzheimer's pilot published: plasma 24-hydroxycholesterol rises on 50 and 200 mg daily.
5. 2025JCI Insight paper reports survival gain in a human-PrP sporadic CJD mouse model.
6. 2026Xuanwu Hospital phase 3 efavirenz trial starts (14 April).
7. 2028Estimated primary completion of the Xuanwu trial.