The corneal endothelium (CE) is a single, highly metabolic layer of hexagonal cells that constitute the innermost layer of the cornea. The CE maintains corneal transparency by actively pumping ions into the anterior chamber thereby facilitating the exit of water to maintain deturgescence. The regenerative capacity of the CE is limited in humans, nonhuman primates and dogs such that loss of a critical number or function of endothelial cells can lead to CE decompensation, corneal edema, vision impairment, and in chronic cases, painful corneal ulcers.Non-human primates (NHP), including rhesus macaques (Macaca mulatta), are highly valuable animal models to study ophthalmic diseases due to their similar ocular development, anatomy, and physiology to humans. Establishment of reference values for corneal thickness and corneal endothelial cell density, as well as their association with factors such as age or sex are critical to better understand the advantages and limitations of rhesus macaques as an animal model for the study of corneal endothelial diseases and therapeutics directed towards these important cells. In Chapter 2 of this dissertation, we determined normal ranges of corneal thickness and endothelial cell density as well as their association with age, sex, weight in 144 rhesus macaques from the California National Primate Research Center (CNPRC).
Corneal endothelial dystrophy (CED) is a bilateral, progressive disease in dogs characterized by premature degeneration and loss of corneal endothelial cells, which leads to corneal edema, bullous keratopathy and recurrent corneal ulceration. Secondary infectious keratitis and corneal perforation can occur in advanced cases, necessitating enucleation. In humans, an analogous condition exists, termed Fuchs’ endothelial corneal dystrophy (FECD). Currently, corneal transplantation is the only definitive treatment for FECD. However, this surgical procedure is rarely performed in veterinary medicine due to the lack of donor tissue, price, and risk of complications. In humans, topical rho-associated coiled-coil kinase (ROCK) inhibitors are in clinical trials to assess their efficacy in accelerating endothelial regeneration and preventing bullous keratopathy in FECD-affected patients. We recently completed a prospective, open label clinical trial demonstrating that the ROCK inhibitor, ripasudil, delayed progression of CED in dogs with early disease. However, adherence to this medication was difficult in some cases as ripasudil requires 4 times a day application. Netarsudil 0.02% is an FDA approved ROCK inhibitor for the treatment of glaucoma in humans that only requires twice daily administration. In Chapter 3 of this dissertation, we provide an interim analysis of for this clinical trial that tests the efficacy of topical netarsudil 0.02% as a treatment for CED in dogs.
The pathogenesis of FECD is complex, and both genetic and non-genetic factors are known to play critical roles. A retrospective study from our laboratory found that Boston Terriers are overrepresented among the breeds that have CED, suggesting the presence of an underlying genetic predisposition in this breed. The identification of a genetic mutation or variant associated with CED would facilitate the development of genetic testing to inform owners, veterinarians, and Boston terrier breeders on which dogs may be on risk of developing CED. In Chapter 4 of this dissertation is a genome-wide association study (GWAS) to identify risk associated loci for CED in the Boston Terrier.
Other causes of CE cell damage or degeneration include anterior uveitis, glaucoma, intraocular surgery, lens luxation, diabetes mellitus, canine adenovirus-1 infection (CAV-1), senility, and corneal endotheliitis. Corneal endotheliitis is the result of primary inflammatory damage to the CE that typically manifests with endothelial loss, corneal edema, keratic precipitates, and inflammatory debris on the endothelium. Corneal endotheliitis as a primary entity is uncommon in canine patients, and some of the clinical signs and imaging features can be misinterpreted by the clinician. In Chapter 5, we describe the clinical findings, advanced imaging characteristics, and treatment of four canine endotheliitis cases. The purpose of this chapter was to inform the clinicians of those clinical and imaging features that are indicative of corneal endotheliitis, as well as the response we have observed in our patients to different treatments.
In summary, this dissertation analyzes different aspects of the physiology and disease of the corneal endothelium in comparative ophthalmology. Namely, we define standard corneal parameters in primates without ocular disease, explore the efficacy and safety of a new medical treatment for canine CED, investigate the genetics of CED in the Boston terrier, and offer a review on the clinical presentation and imaging characteristics of canine corneal endotheliitis.
