Exploiting tear film resources to fight corneal pathologies – TeFiCoPa

The cornea, transparent tissue protecting the eye, is instrumental to a clear vision. It is composed of a stratified epithelium supported by a mesenchymal stroma. While the stroma is mainly acellular, the epithelium forms the barrier protecting the eye chamber. This epithelial compartment undergoes a life-long renewal. The cornea homeostasis is instrumental to clear sight. Injuries, genetic syndromes, or diseases can lead to a loss of cornea transparency, and ultimately loss of vision. Diseases affecting the cornea are a major cause of blindness and visual impairment worldwide, second only to cataract. Around 28 million people suffer from uni- or bi-lateral corneal blindness worldwide. Epidemiological studies reporting corneal blindness incidence in France are scarce. However, an indirect way to assess the incidence of severe corneal disease in France are corneal transplant data recorded by two systems: CRISTAL, recording every tissue taken from a deceased donor, and the GLAC waiting list gathering every patient awaiting corneal transplant and corneal transplant performed. According to these data sources in 2019 we can approximate an incidence of corneal visual impairment in France is about 10/100,000 persons. This approximation does not consider the early onset of corneal opacifications, such as seen in dry eye, impacting 1/3 of the elderly. Investigating new strategies to prevent or rescue corneal defects is necessary for the protection of sight.
To deepen the knowledge on corneal defect treatments, it is of interest to keep in mind three crucial aspects of corneal physiology, all inherent to corneal most important feature, its transparency. First, due to the lack of vascularization, nutrients have another route to reach the ocular surface, the tear film. Second, to maintain a proper epithelial renewal, corneal homeostasis requires a coordinated cell turn-over. Finally, corneal epithelium is the most non-neural innervated tissue in the body, enabling a fast response to any damage. These three elements together form the corneal microenvironment, which is crucial to corneal physiology, and when an element is out of balance, then corneal pathologies can set, progressively or abruptly. Among these three elements of the corneal microenvironment, the tear film is of particular interest. While being composed of three layers, the aqueous one, secreted by the lacrimal gland, is the largest and contains all nutrients and growth factors necessary for corneal homeostasis. Moreover, after corneal damage, the tear film composition changes to support corneal repair and its return to a physiological situation. The most prevalent tear film defect is the dry eye disease, affecting up to 30% of the elderly, and leading to a progressive opacification of corneal epithelium. Up to date, while little is known about the cytokines secreted in tears and supporting corneal physiology, they represent an asset for the modulation of corneal physiology in situ.
The goal of this project is to identify and validate therapeutic targets within the tear film in corneal pathophysiological contexts for upcoming clinical trials. Three axes will be developed. The first axis will be the analysis of murine corneal microenvironment modulations in pathological contexts. Four pathological contexts were chosen, corresponding to most patients having corneal defects. The second axis will be the identification of biomarkers and cytokines from human tear film. Tears, collected at different times before and after corneal healing, will be analyzed by targeted and non-targeted proteomics techniques. The final focus will be the validation of the impact of potential therapeutic targets. We will develop a validation pipeline based on in vivo animal models, and ex vivo bioengineered human hemicorneas. This proposed strategy will unravel therapeutic targets for subsequent clinical trials.