Topical Ripasudil for the Treatment of Primary Corneal Endothelial Degeneration in Dogs

Abstract

Purpose The purpose of this study was to evaluate the tolerability and efficacy of topical rho-kinase inhibitor ripasudil in the treatment of primary corneal endothelial degeneration (PCED) in dogs. Methods Twenty-one eyes of 12 client-owned, PCED-affected dogs received topical ripasudil 4 times daily. Ophthalmic examination, ultrasonic pachymetry (USP), Fourier-domain optical coherence tomography (FD-OCT), and in vivo confocal microscopy were performed at baseline and 1, 3, 6, and 12 months. Effects of treatment on corneal thickness, corneal edema extent, and endothelial cell density (ECD) were evaluated by repeated-measures ANOVA or Friedman test. Individual eyes were classified as improved, progressed, or stable at 12 months using clinical response criteria. Kaplan-Meier curves and log-rank test were used to compare ripasudil-treated eyes to age-, breed/size-, and disease stage-matched historical controls. Results During treatment, 12 dogs developed conjunctival hyperemia, 4 demonstrated reticular bullous epithelial edema, and 2 developed corneal stromal hemorrhage. No adverse event necessitated permanent cessation of ripasudil. Central corneal thickness measured by USP significantly progressed from baseline to 12 months. Corneal thickness by FD-OCT, ECD, and edema extent did not differ over time. Considered individually, 5 eyes improved, 8 remained stable, and 8 progressed. The log-rank test found less edema progression in ripasudil-treated eyes compared to historical controls. Conclusions Ripasudil was well-tolerated in PCED-affected dogs. Response to therapy varied; 62% of eyes showed improved or stable disease whereas 38% progressed. Ripasudil-treated eyes progressed more slowly than historical controls. Translational Relevance Topical ripasudil offered a therapeutic benefit in a subset of patients using a canine model of endothelial degeneration, which may guide future trials in humans.

Squishy matters – Corneal mechanobiology in health and disease

“…This premise is further supported by our recent study demonstrated that ripasudil administration for 1 year in dogs with primary corneal endothelial degeneration improved or stabilized disease in 62% of patients ( Fig. 27 ) ( Michalak et al, 2022 ). In aggregate, there is a pressing need to study how ROCK inhibitors modulate ECM deposition and remodeling in corneal endothelial cells from FECD patients in vitro as well as in relevant animal models and clinical trials.…”

“…Further characterization of this condition in three at-risk breeds, Boston Terriers, German Shorthaired and Wirehaired Pointers, revealed reduced ECD, endothelial polymegathism and pleomorphism, progressive corneal edema with increased thickness, a thickened DM-endothelial complex and guttae-like lesions ( Shull et al, 2018 ; Thomasy et al, 2016a ). The model has been utilized to investigate a novel surgical procedure ( Horikawa et al, 2016 ) and the ROCK inhibitor ripasudil ( Michalak et al, 2022 ) over a 1-year period since CED progresses more quickly in canine patients than FECD does in humans. In aggregate, the striking similarities between FECD and CED combined with the similar environments that dogs and humans reside in suggest that successful therapies for CED may be more likely to translate successfully to FECD patients than those tested solely in healthy animal models with induced corneal endothelial injury.…”

“…Seventeen ripasudil-treated eyes and 17 untreated, age- and breed/size-matched historical controls were included in the analysis. Adapted from Michalak, S.R., Kim, S., Park, S., Casanova, M.I., Bowman, M.A.W., Ferneding, M., Leonard, B.C., Good, K.L., Li, J.Y., Thomasy, S.M., 2022 . Topical Ripasudil for the Treatment of Primary Corneal Endothelial Degeneration in Dogs.…”