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E2012-induced cataract and its predictive biomarkers
Kyoko Nakano-Ito1, Yasuhiro Fujikawa, Taro Hihara
1* Biopharmaceutical Assessments Core Function Unit and.
Abstract:
E2012, a gamma secretase modulator without affecting Notch processing, aimed at Alzheimer's disease by reduction of amyloid β-42, induced cataract following repeated doses in the rat. Cataract appeared first at week 10-11 of treatment as a posterior subcapsular area with granular/punctate opaque or shiny dots along the suture line, characterized histologically as lenticular fiber degeneration, which eventually coalesced to form a triangular or circular opacity. It was associated with prolonged and sustained elevation of lenticular desmosterol (24-dehydrocholesterol), the final precursor of cholesterol, and decrease in lenticular cholesterol. In vitro studies to investigate the effect of E2012 on cholesterol metabolism demonstrated that E2012 inhibits 3β-hydroxysterol Δ24-reductase (DHCR24) at the final step in the cholesterol biosynthesis. In vivo lenticular concentration of E2012 after 13-week repeated dose with cataract was well above those where inhibition was observed in vitro. There was no cataract formation at doses where desmosterol did not accumulate in the lens. The elevation of desmosterol and decreased cholesterol levels were also seen in the liver and plasma and preceded those in the lens. These results demonstrate that E2012 induces cataract in the rat by inhibiting DHCR24 at the final step of cholesterol synthesis with associated elevation in desmosterol within the lens, preceded by desmosterol changes that would serve as a predictive safety biomarker for lenticular opacity.
Insights
The Alzheimer's drug E2012 caused cataracts in rats by inhibiting cholesterol synthesis, specifically DHCR24. Elevated desmosterol levels in the lens and plasma served as a predictive biomarker for this adverse effect.
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.
