Inhibiting neovascularization for corneal wound healing

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Project Summary The healthy cornea is an avascular tissue which is a requirement for optical clarity and good vision. Diseases in which the optical clarity of the cornea is lost are the third most common cause of blindness worldwide. Various disease conditions, such as corneal injury, can result in inflammation and the pathological ingrowth of vessels into the cornea, a process known as corneal neovascularization (CNV). Prevention of vascular ingrowth is imperative in maintaining the health and transparency of the cornea. We have previously demonstrated that MG53, a tissue repair gene, can promote corneal wound healing in both the epithelium and stroma. We recently discovered that MG53 can modulate corneal inflammation and vascularization. An approach that can functionally target multiple steps in corneal wound healing may have the potential to significantly improve healing outcomes, leading to novel therapeutic options. MG53 is present in the human tear film, aqueous humor, and corneal epithelial cells, supporting its potential function in corneal homeostasis and wound healing. We show that genetic ablation of MG53 leads to pronounced corneal inflammation and neovascularization as compared to wild type littermates. Using in vivo corneal injury models, we find that MG53 promotes corneal transparency by reducing acute inflammation and post-injury vascularization. Biochemical and animal studies revealed that pyroptosis, a cytolytic cell death, is a novel pathway involved in post-injury CNV, as observed in gasdermin D, a key molecule of pyroptosis, knockout corneas which were resistant to injury-induced CNV. Further, MG53 can inhibit pyroptosis by interacting with gasdermin D, preventing its activation. In vivo corneal wounding experiments revealed corneal pyroptosis followed neutrophil infiltration. Antibody depletion of neutrophils completely abolished post-injury pyroptosis, suggesting infiltrating neutrophils undergoing pyroptosis trigger secondary corneal injury and CNV. Indeed, when irradiated WT recipient mice received bone marrow (BM) transplantation from GsdmD-/- mice, they displayed enhanced corneal healing as compared to mice that received BM from WT mice. Experiments outlined in this project are centered on testing the hypothesis that neutrophil pyroptosis is a key pathway that mediates corneal inflammation and CNV following injury; MG53 can inhibit pyroptosis via preventing activation of GasdmD, thus rhMG53 can be used as an effective means to treat corneal injury. We envision that MG53 can be applied to promote corneal healing and prevent neovascularization after injury. The outcome of this research shall have significant translational value in developing potentially effective therapies to treat corneal injury and neovascularization associated with corneal disease.