Progressive corneal endothelial disease eventually leads to corneal edema and vision loss due to the limited regenerative capacity of the corneal endothelium in vivo and is a major indication for corneal transplantation. Despite the relatively high success rate of corneal transplantation, there remains a pressing global clinical need to identify improved therapeutic strategies to address this debilitating condition. To evaluate the safety and efficacy of novel therapeutics, there is a growing demand for pre-clinical animal models of corneal endothelial dysfunction. In this review, experimentally induced, spontaneously occurring and genetically modified animal models of corneal endothelial dysfunction are described to assist researchers in making informed decisions regarding the selection of the most appropriate animal models to meet their research goals.

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Purpose We sought to define the role of Wwtr1 in murine ocular structure and function and determine the role of mechanotransduction in Fuchs’ endothelial corneal dystrophy (FECD), with emphasis on interactions between corneal endothelial cells (CEnCs) and Descemet's membrane (DM). Methods A Wwtr1 deficient mouse colony was established, and advanced ocular imaging, atomic force microscope (AFM), and histology/immunofluorescence were performed. Corneal endothelial wound healing was assessed using cryoinjury and phototherapeutic keratectomy in Wwtr1 deficient mice. Expression of WWTR1 /TAZ was determined in the corneal endothelium from normal and FECD-affected patients; WWTR1 was screened for coding sequence variants in this FECD cohort. Results Mice deficient in Wwtr1 had reduced CEnC density, abnormal CEnC morphology, softer DM, and thinner corneas versus wildtype controls by 2 months of age. Additionally, CEnCs had altered expression and localization of Na/K-ATPase and ZO-1. Further, Wwtr1 deficient mice had impaired CEnC wound healing. The WWTR1 transcript was highly expressed in healthy human CEnCs comparable to other genes implicated in FECD pathogenesis. Although WWTR1 mRNA expression was comparable between healthy and FECD-affected patients, WWTR1/TAZ protein concentrations were higher and localized to the nucleus surrounding guttae. No genetic associations were found in WWTR1 and FECD in a patient cohort compared to controls. Conclusions There are common phenotypic abnormalities seen between Wwtr1 deficient and FECD-affected patients, suggesting that Wwtr1 deficient mice could function as a murine model of late-onset FECD. Despite the lack of a genetic association between FECD and WWTR1 , aberrant WWTR1 /TAZ protein subcellular localization and degradation may play critical roles in the pathogenesis of FECD.

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