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

项目摘要 眼睛表面对硫磺芥末(SM)暴露特别敏感，导致角膜 皮损、浮肿、溃疡、新生血管和视力丧失。Synedgen已经开发出一种 一类无毒的聚氨基葡萄糖衍生物，具有抑制炎症、减少 感染，并促进粘膜表面的愈合。这些分子被假定为起作用 直接在角膜表面暴露SM后，减少下游的激活 一次损伤后的炎症，从而减少二次损伤，水肿， 新生血管和视力丧失。 Synedgen的筛选计划使用体外方法识别先导化合物以取得进展 变成动物模型。兔眼停留时间、分布和耐受性将是 在SM眼部暴露的概念验证研究之前进行评估，该研究使用剂量和 暴露时间以反映导致新生血管和纤维化的双相损伤。 各种眼上皮细胞的单层被确定为适合于高眼压 吞吐量筛选和第一轮测试的分子达到了所有里程碑。而上皮性 在靶向分析中，细胞对于确定分子的活性是有用的， 不同细胞对刺激分子和合并素分子的细胞反应表明 这些细胞独立地可能无法预测角膜表面的反应。为了更好地 选择最佳候选分子以推进动物研究，本附录建议 使用更接近地反映预期的形态和反应的3D组织模型 来自人类的角膜。

Project Summary The ocular surface is uniquely susceptible to Sulfur Mustard (SM) exposure, resulting in corneal lesions, edema, ulcerations, neovascularization and 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. 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. Synedgen's screening program uses in vitro methods to identify lead compounds to advance into animal models. Ocular residency times, distribution and tolerability in rabbits will be assessed prior to a proof-of-concept study with SM ocular exposure that uses dose and exposure time to reflect a biphasic injury that results in neovascularization and fibrosis. Monolayers of a variety of ocular epithelial cells were determined to be suitable for the high throughput screens and the first round of molecules tested met all milestones. While epithelial cells are useful for determining activity of the molecules in targeted assays, the variance in cellular response between the different cells to both stimulus and Synedgen molecules suggests that these cells independently might not predict the response of the corneal surface. To better select the best candidate molecule to advance into animal studies, this supplement proposes to use a 3D tissue model that more closely reflects the morphology and responses that expected from the human cornea.