E2012-induced cataract and its predictive biomarkers.

Area of Science:

• Pharmacology
• Ophthalmology
• Biochemistry

Background:

• E2012, a gamma secretase modulator, targets Alzheimer's disease by reducing amyloid β-42.
• Gamma secretase modulators can have off-target effects, necessitating safety evaluations.

Purpose of the Study:

• To investigate the mechanism by which E2012 induces cataract formation in rats.
• To identify potential biomarkers for E2012-induced lenticular toxicity.

Main Methods:

• Repeated dose toxicity study in rats with E2012 administration.
• Ophthalmic examinations and histological analysis of the lens.
• Biochemical analysis of cholesterol and desmosterol levels in the lens, liver, and plasma.
• In vitro studies to assess the effect of E2012 on DHCR24 activity.

Main Results:

• E2012 treatment led to the development of posterior subcapsular cataracts.
• Cataract formation was associated with elevated lenticular desmosterol and decreased cholesterol.
• E2012 was found to inhibit 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme responsible for the final step of cholesterol biosynthesis.
• Systemic elevation of desmosterol preceded its accumulation in the lens, suggesting a predictive biomarker.

Conclusions:

• E2012 induces cataract in rats through the inhibition of DHCR24, leading to altered lens cholesterol metabolism.
• Elevated desmosterol levels, both systemically and in the lens, are a predictive safety biomarker for E2012-induced cataract.
• These findings highlight the importance of monitoring cholesterol metabolism during the development of drugs targeting amyloid β-42.