Corneal Confocal Microscopy: a Surrogate Endpoint for Neurodegeneration in Clinical Trials


CCM versus Conventional Endpoints in Animal Models

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Confocal microscopy to visualize corneal nerves has been applied to many non-human species, from cats and dogs to the eagle owl, vulture and yellow-breasted macaw.Amongst laboratory animals, both rats and mice exhibit quantifiable nerves in the sub-basal nerve plexus and deeper stroma that can be viewed iteratively across the course of a disease. Diabetic rodents develop a progressive reduction in nerve density in the sub-basal nerve plexus that precedes the stroma, indicative of a distal neuropathy and onset of reduced density either parallels or precedes other indices of small and large fiber neuropathy. Reduced corneal nerve density in diabetic mice is prevented by topical insulin delivery to the eye that did not impact systemic hyperglycemia, suggesting a role for loss of trophic support.Reduced corneal nerve density in diabetic rodents can also be prevented and/or reversed by a variety of agents applied topically to the eye and we find this to be a useful bridging assay between in vitro screening of potential therapeutics and chronic systemic delivery studies. Other than diabetes, we have identified reduced corneal nerve density in rodent models of chemotherapy and HIV protein induced peripheral neuropathy and tauopathy, with the latter exhibiting a somatofugal progression.