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

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Project Summary: 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. This effort will study five molecules from the polyglucosamine derivatives library. The molecules are hypothesized to act directly at the corneal surface after SM exposure to reduce the activation of downstream inflammation after primary injury, consequently reducing secondary damage, edema, neovascularization and vision loss. The molecules will be synthesized, validated and compared in in vitro screens to assess activity in wound healing and inflammatory pathways shown to correlate in vitro activity with in vivo physiologic response in SM corneal injury. The most efficacious molecule will be selected from these in vitro screens as the lead compound and produced at a larger scale and with a fluorescein label. Ocular residency times, distribution and tolerability in rabbits will be assessed prior to a proof-of-concept preliminary study with SM ocular exposure. The SM dose and exposure time will be selected to reflect a biphasic injury that results in longer term neovascularization and fibrosis. Multiple doses of the lead compound will be tested along with observations of in-life clinical outcomes, histopathology, immunohistopathology, gene expression and protein expression. Should the lead compound be biologically efficacious, additional dosing and administration efficacy studies on different SM exposures as well as preclinical safety/toxicity studies will be performed in anticipation of a continued drug development program for FDA approval.