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.

Grant Number: 5U01EY032973-04
NIH Institute/Center: NIH
Principal Investigator: Heather Chandler