Evaluation of the feasibility of caspase inhibitor eye drops as a treatment for Fuchs endothelial corneal dystrophy in a mouse model

Abstract

Purpose : We previously reported that caspase inhibitors suppress extracellular matrix production and cell death using a cell model derived from patients with Fuchs corneal endothelial dystrophy (FECD) (Endo M, et al. ARVO 2017). The aim of this study was to examine the feasibility of using a caspase inhibitor as a drug for FECD in FECD-model mice.

Methods : Col8a2^Q455K/Q455K mice, kindly provided by Dr. Jun AS, were used as the FECD model. Emricasan, a caspase inhibitor, was diluted to 0.5% and administered twice daily as an eye drop in the right eye of the FECD model mice. Emricasan was administered twice daily from 8 weeks of age until 28 weeks of age (n=68). As a control, the vehicle was administered (n=32). After 20 and 28 weeks of administration, corneal endothelium was observed using a contact specular microscope. The percentage of the guttae area, corneal endothelial cell density (ECD), hexagonality, and coefficient of variation were calculated. Corneal endothelium was obtained at 28 weeks of age, and RNA sequencing (RNA-Seq) was conducted to analyze differentially expressed genes (DEGs).

Results : At 20 weeks of age, the guttae area percentage was 1.00 ± 0.09 % in the control group and significantly smaller, at 0.75 ± 0.05 %, in the emricasan group (p=0.031). At 28 weeks, the ECD was significantly higher in the emricasan group than in the controls (1778 ± 19 cells/mm² and 1706 ± 15 cells/mm², respectively) (p<0.01). The hexagonality was significantly higher in the emricasan group than in the controls (44.0 ± 0.4% and 40.9 ± 1.0 %, respectively) (p<0.01). The coefficient of variation was significantly lower in the emricasan group than in the controls (0.262 ± 0.004 and 0.293 ± 0.008, respectively) (p<0.01). RNA-Seq identified that the expression of 1,435 genes (401 upregulated and 1,034 downregulated genes) was significantly altered in the corneal endothelium of the emricasan group compared to the control group.

Conclusions : Caspase inhibitor eye drops suppressed guttae formation and loss of endothelial cells in the FECD model mice. This non-clinical research supports the possibility that caspase inhibitors are potential drug candidates for treating FECD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.