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

项目概述：硫芥（SM）已被用作化学武器， 在不稳定地区生产和使用SM增加了这种制剂可能用于以下目的的风险： 针对平民造成大规模伤亡或针对军事人员的蓄意恐怖袭击。 眼表对SM特别敏感，导致角膜病变、水肿、溃疡， 新生血管形成和视力丧失。眼SM损伤的推荐治疗方法是切除 使用洗眼液，然后用抗生素进行局部治疗， 皮质类固醇（抗炎剂）、镇痛剂和人工泪液。然而，需要 仍然是产品，改善愈合时间，减少视力丧失，并防止潜在的 此外，目前没有美国食品和药物管理局批准的用于SM的药物 诱发眼损伤，以促进愈合和减少视力丧失。 Synedgen开发了一类无毒的聚葡萄糖胺衍生物， 抑制炎症、减少感染和改善粘膜表面愈合。这一努力将 研究来自聚葡糖胺衍生物库的五种分子。所述分子 假设在SM暴露后直接作用于角膜表面，以减少 在原发性损伤后的下游炎症，从而减少继发性损伤，水肿， 新生血管形成和视力丧失。这些分子将被合成、验证和比较 在体外筛选中评估伤口愈合和炎症途径的活性， SM角膜损伤中的体外活性与体内生理反应相关。最 将从这些体外筛选中选择有效的分子作为先导化合物， 以更大规模生产并带有荧光素标记。眼部停留时间、分布和 在SM眼部概念验证初步研究之前，将评估家兔的耐受性 exposure.选择SM剂量和暴露时间以反映导致的双相损伤 长期的新血管形成和纤维化。将测试多剂量的先导化合物 沿着活体临床结局、组织病理学、免疫组织病理学、基因 表达和蛋白质表达。如果先导化合物是生物有效的， 关于不同SM暴露量的额外给药和给药有效性研究，以及 临床前安全性/毒性研究将在预期的持续药物开发中进行 FDA批准的程序。

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.