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

鉴定用于局部治疗硫芥损伤的先导化合物，以减少眼部损伤并改善视力。

基本信息

批准号：
10221889
负责人：
Shenda Baker
金额：
$ 7.45万
依托单位：
SYNEDGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2022-07-31
项目状态：
已结题

项目摘要

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.

项目概要眼表特别容易受到芥子气 (SM) 暴露的影响，导致角膜损伤病变、水肿、溃疡、新生血管和视力丧失。 Synedgen 开发了一种一类无毒的聚葡萄糖胺衍生物，具有抑制炎症、减少炎症的能力感染，并改善粘膜表面的愈合。假设这些分子起作用 SM曝光后直接作用于角膜表面，以减少下游的激活原发性损伤后的炎症，从而减少继发性损伤、水肿，新血管形成和视力丧失。 Synedgen 的筛选计划使用体外方法来识别先导化合物以推进进入动物模型。兔子的眼部驻留时间、分布和耐受性将在使用 SM 眼部暴露进行概念验证研究之前进行评估，该研究使用剂量和暴露时间反映导致新血管形成和纤维化的双相损伤。多种眼上皮细胞的单层被确定适合高通量筛选和第一轮测试的分子达到了所有里程碑。而上皮细胞可用于确定靶向测定中分子的活性，不同细胞对刺激物和 Synedgen 分子之间的细胞反应表明这些细胞可能无法独立预测角膜表面的反应。为了更好选择最佳候选分子进入动物研究，本补充建议使用更接近地反映预期形态和反应的 3D 组织模型来自人类角膜。