First Aid Medicine to Treat Vesicant Induced Corneal Injury

Project Summary Sulfur mustard (SM) and nitrogen mustard (NM) are potent chemical threats that cause damage to the cornea, including acute photophobia and corneal lesions followed by loss of limbal stem cells (LSCs) and prolonged ulceration and vascularization. Therapeutic approaches targeting both the acute and prolonged phases of SM/NM toxicity can potentially provide effective measures to counteract corneal injuries. We provide novel findings that support the benefits of MG53, a tissue repair protein, in treating vesicant-induced corneal wounds. Compared with wild type mice, mg53-/- littermates show delayed corneal re-epithelialization, increased vascularization and conjunctivatization following NM exposure, all hallmarks of LSC deficiency. Further, transgenic mice with sustained elevation of MG53 are resistant to NM-induced corneal injury. We find that the recombinant human MG53 protein (rhMG53) protects against injury to LSCs and corneal epithelial cells to preserve cornea integrity during NM exposure. We also know that MG53 protein is naturally present in the tear film and aqueous humor, supporting the physiology of MG53 in corneal homeostasis and the safe nature of using rhMG53 to treat corneal injuries. The goal of this U01 project is to develop rhMG53 as a potential effective protein therapeutic to mitigate the acute and prolonged phases of vesicant corneal injury. We will formulate rhMG53 for ocular application as a first-aid medicine that can be stockpiled as a medical reserve and rapidly deployed to affected patients in the event of chemical threats. In vitro and ex vivo studies will be performed to elucidate the mechanistic action of MG53 in protecting against NM-induced injury to LSCs and corneal epithelia. Validation studies will be conducted with rhMG53 in mouse and rabbit models of vesicant-induced corneal injuries to determine the therapeutic efficacy and safety windows of rhMG53 in rescuing cornea function. Overall, this U01 program provides a unique opportunity to advance the biology of MG53 into an important counteract therapeutic.