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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：
10019558
负责人：
Shenda Baker
金额：
$ 32.2万
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

来源：
https://reporter.nih.gov/project-details/10019558
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 Epithelium 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

项目摘要

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.

项目概述：硫芥菜（SM）已被用作化学武器