Identification of lead compounds to topically treat sulfur mustard injury to reduce ocular damage and improve vision.

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Abstract Sulfur Mustard (SM) has been employed as a chemical weapon, and production and use of SM in unstable regions heightens the risk that this agent could be used in a deliberate terrorist attack against civilians causing mass casualties or against military personnel. The ocular surface is uniquely susceptible to SM resulting in corneal lesions, edema, ulcerations, neovascularization and vision loss. The recommended treatment for ocular SM injury is removal of remaining agent using an eye wash, followed with topical treatments with antibiotics, corticosteroids (anti-inflammatory agents), analgesics and artificial tears. However, a need remains for products that improve healing times, reduce vision loss, and prevent the latent keratitis. Further, there are currently no US Food and Drug Administration approved drugs for SM induced ocular injuries to improve healing and reduce vision loss. Synedgen has developed a class of non-toxic polyglucosamine derivatives with the ability to suppress inflammation, reduce infection, and improve healing at mucosal surfaces. Having seen significant healing and anti-inflammatory effects with a particular guanidium modified glycopolymer in a rabbit ocular alkali burn, other derivatives were hypothesized to have potentially better ocular characteristics. This effort proposed three aims to identify and test a treatment for SM ocular injury: 1) synthesize new molecules, 2) down select in in vitro models of inflammation, healing and adhesion and 3) optimize dose in a rabbit model of SM ocular injury. The first two completed aims generated two strong candidate molecules for the SM study proposed in Aim 3. Given successful identification of lead molecules to initiate the final aim of the study, discussions were initiated with the contractor for the proposed SM rabbit study. Because that study was quoted over three years ago, the cost assumptions no longer hold. Although aspects of the study were reduced or eliminated, completion of the study with potentially statistically significant results requires additional funds. This supplemental proposal describes the study design to support the request.