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。

• 批准号: 10228005
• 负责人: Shenda Baker
• 金额: $ 31.93万
• 依托单位: SYNEDGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228005
• 关键词: Adrenal Cortex Hormones; Advanced Development; Analgesics; Animals; Anti-Inflammatory Agents; Antibiotics; Artificial Tears; Basement membrane; Biological; Biological Assay; Biological Markers; Biopsy; Blindness; Cells; Cellular Assay; Certification; Chemical Weapons; Chemicals; Cicatrix; Cities; Clinical; Contralateral; Control Groups; Cornea; Corneal Injury; Corneal Neovascularization; Corneal Opacity; Corneal Ulcer; Dinoprostone; Dose; Edema; Epithelial; Epithelial Cells; Excision; Exposure to; Eye; Eye Injuries; Eyelid structure; Fibrosis; Fluorescein; Fluorescence; Gene Expression; Gene Proteins; Glycocalyx; High Pressure Liquid Chromatography; Histopathology; Human; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Kansas; Keratitis; Label; Lead; Lesion; Libraries; Life; Measurement; Mechlorethamine; Metalloproteases; Military Personnel; Modeling; Molecular Weight; Mucous Membrane; Mustard Gas; Natural regeneration; New Zealand; Occupational Exposure; Oryctolagus cuniculus; Outcome; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Production; Program Development; Proteins; Recurrence; Redness; Research; Residencies; Risk; Role; Schedule; Solubility; Structure; Surface; Swelling; System; Terrorism; Testing; Thick; Time; Tissue Banks; Tissues; Topical application; Toxic effect; Ulcer; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vesicants; Vision; Visual impairment; absorption; alkalinity; analog; appropriate dose; burn model; corneal epithelium; corneal regeneration; corneal scar; cyclooxygenase 2; cytokine; drug development; efficacy study; experience; healing; improved; in vitro activity; in vitro testing; in vivo; in vivo evaluation; irritation; lead optimization; lewisite; mass casualty; neovascularization; notch protein; novel; ocular surface; preclinical safety; prevent; programs; protein expression; response; screening; therapeutic development; visual tracking; wound healing

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.

项目概要：硫芥（SM）已被用作化学武器，并且 在不稳定地区生产和使用 SM 会增加该剂用于以下地区的风险： 蓄意针对平民或军事人员的恐怖袭击，造成大规模人员伤亡。 眼表特别容易受到 SM 的影响，导致角膜损伤、水肿、溃疡、 新血管形成和视力丧失。眼部 SM 损伤的推荐治疗方法是切除 使用洗眼液清除剩余药剂，然后使用抗生素进行局部治疗， 皮质类固醇（抗炎药）、镇痛药和人工泪液。然而，需要 仍然是那些能够缩短愈合时间、减少视力丧失并防止潜在视力丧失的产品 此外，目前美国食品和药物管理局还没有批准治疗 SM 的药物 诱发眼部损伤，以促进愈合并减少视力丧失。 Synedgen 开发了一类无毒的聚葡萄糖胺衍生物，能够 抑制炎症、减少感染并改善粘膜表面的愈合。这项努力将 研究聚葡萄糖胺衍生物库中的五种分子。分子是 假设在 SM 暴露后直接作用于角膜表面，以减少角膜的激活 原发性损伤后的下游炎症，从而减少继发性损伤、水肿、 新血管形成和视力丧失。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 将 SM 角膜损伤的体外活性与体内生理反应相关联。最 将从这些体外筛选中选择有效的分子作为先导化合物并 大规模生产并带有荧光素标签。眼部驻留时间、分布 在使用 SM eye 进行概念验证初步研究之前，将评估兔子的耐受性 接触。 SM 剂量和暴露时间的选择应反映所导致的双相损伤 长期来看，新生血管形成和纤维化。将测试先导化合物的多个剂量 以及对生活中临床结果、组织病理学、免疫组织病理学、基因的观察 表达和蛋白质表达。如果先导化合物具有生物学功效， 针对不同 SM 暴露的额外剂量和给药功效研究以及 将进行临床前安全性/毒性研究以预期持续的药物开发 FDA 批准计划。