Sulfur mustard (SM), nitrogen mustard (NM) and lewisite (LEW) are vesicating agents that are among the most potent chemical weapons, and are the current focus for the development of countermeasures. In the past, lack of NM-, SM- and LEW-induced ocular injury models to identify the mechanisms of toxicity and therapeutic targets has been a major impediment to developing effective therapies. However, in recent years, we have successfully developed and characterized all three vesicants (NM, SM, and LEW)-induced ocular (corneal) injury models in vivo in rabbits, relevant to humans. Also, we identified an increased expression of COX-2 and iNOS, VEGF, and MMP-9 as possible mediators of inflammation, neovascularization (NV) and microvesication, respectively, in ocular injuries by these three vesicants. This is an important finding as it suggests that an agent effective against the ocular injury induced by one of these vesicants would also be effective against the others. Indeed, in our proof of concept efficacy studies, we demonstrated that dexamethasone (DEX, an FDA approved drug) is an effective agent in ameliorating all three vesicants (NM, SM, LEW)-induced ocular injuries in vivo in rabbits. This is a significant finding because the regulatory pathway for this new use of DEX is much easier to pursue, since the new use application for DEX would be able to rely on the existing safety and efficacy data of the reference DEX application, leading to less data needed for the application and an easier approval pathway. An advantage of DEX, based on review by the CU technology transfer office, is that there are no competitive intellectual property (IP) barriers to bringing this new use to market. The further advantage of using DEX is that we do not need to generate additional IP in order to create a commercial product, as DEX is available at a low cost from multiple sources as a generic and branded prescription drug, and will have no shortages in times of a medical emergency. Together, based on our completed studies and clear regulatory pathway forward, our hypothesis is that DEX has strong potential to reverse both mustard- and arsenical-induced ocular injury, and that as a promising targeted `optimized lead' therapeutic, it can be easily available for human use in medical emergency.
Our specific aims are to: 1) optimize dosing frequency of DEX to treat vesicating agents-induced in vivo ocular injury in rabbits; 2) evaluate the most effective DEX treatment regimen to counteract vesicating agents-induced corneal injury in human corneal organ culture; 3) define the molecular mechanism of DEX in rescuing vesicating agents-induced ocular injury; and 4) develop and follow regulatory strategies for approval of DEX indication as an effective countermeasure against vesicating agent-induced ocular injury. Completion of our aims is anticipated to make dexamethasone ready for next stage of advanced drug development process with a clear path for FDA approval as an effective rescue medication for vesicants-induced ocular injuries.
Despite the imminent threat and devastating ocular injuries by exposure to vesicating agents, effective therapies in case of a mass casualty remain elusive. In recent years, we have successfully developed and characterized nitrogen mustard (NM)-, sulfur mustard (SM)- and lewisite (LEW)-induced corneal injury in rabbit models and have identified dexamethasone (DEX; FDA approved) as a lead countermeasure in ameliorating vesicants-induced corneal injury. In the present application, we propose to optimize the efficacy of a FDA approved clinical topical preparation of DEX in vesicants-induced ocular injury employing in vivo rabbit and ex vivo human cornea culture models to position DEX as an optimized lead therapeutic agent ready for the next stage of advanced drug development process for a clear path to FDA approval as an effective targeted therapy against vesicants-induced ocular injuries in humans.
