Turbo Eye Drops to Treat Ocular Toxicity and Blindness from Sulfur Mustard

涡轮滴眼液治疗硫芥引起的眼部毒性和失明

• 批准号: 10015700
• 负责人: Rajiv Ravindra Mohan
• 金额: $ 70.3万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10015700
• 关键词: Acute; Adverse effects; Affect; Alkylating Agents; Anatomy; Angiogenic Factor; Antidotes; Basement membrane; Biological Assay; Blindness; Cities; Clinical; Clinical Pathology; Collagen Fibril; Consult; Cornea; Corneal Injury; Corneal Ulcer; Data; Development; Diagnostic; Diagnostic Imaging; Dose; Drops; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelium; Euthanasia; Extracellular Matrix Degradation; Eye; Eye Injuries; Eyedrops; FDA approved; Fibrosis; Fluorescein; Formulation; Frequencies; Functional disorder; Funding; Generic Drugs; Goals; Grant; Health; Histologic; Human; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intellectual Property; Iran; Iraq; Joints; Kansas; Keratopathy; Lead; Letters; Literature; Magnetic Resonance Imaging; Measures; Mediating; Methods; Microscope; Modeling; Molecular; Monitor; Mustard Gas; Ocular Pathology; Ophthalmic Solutions; Ophthalmic examination and evaluation; Ophthalmologist; Organ Culture Techniques; Oryctolagus cuniculus; Pain; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Process; Production; Property Rights; Publications; Publishing; Recurrence; Regimen; Research; Safety; Schedule; Scientist; Secure; Syria; Techniques; Technology; Temperature; Terrorism; Testing; Therapeutic Effect; Time; Tissues; Toxic effect; Transmission Electron Microscopy; Treatment Efficacy; Treatment Protocols; Vesicants; Veterinarians; Vision; War; Western Blotting; World War I; base; bench to bedside; corneal epithelium; drug development; effective therapy; high risk; in vivo; in vivo evaluation; limbal; medical countermeasure; meetings; multimodality; neovascularization; novel; side effect; stem cells; tomography; tonometry; tool; vapor

ABSTRACT Sulfur mustard gas (SM), a vesicating and warfare agent, has been used in many wars since World War I; most recently in Syria. SM rapidly penetrates the eye on contact and causes blindness by injuring corneal tissue- organization and function. Clinically, patients show a pathology termed as Mustard Gas Keratopathy that involves severe ocular inflammation, recurrent epithelial-erosions, epithelial-stromal separation limbal stem cell deficiency, corneal ulceration, haze and neovascularization. MGK pathophysiology is biphasic including acute and delayed-onset, and involves multiple mechanisms. We developed a novel, multimodal, non-steroidal topical ophthalmic drops, Turbo Eye Drop (TED), containing 4 FDA-approved generic drugs with differing mode of action, and stable at ambient temperature. Our pilot studies found that topical TED efficaciously treats acute and delayed-onset MGK in rabbits in vivo and human cornea ex vivo without significant side effects. Our central hypothesis is that topical TED treats acute and delayed-onset MGK in vivo by curbing SM-induced early inflammatory responses, extracellular matrix degradation, and production of excessive pro-fibrotic and pro- angiogenic factors without significant side effects. This project tests two novel hypotheses to establish an efficacious and safe topical therapy for acute and delayed-onset MGK in vivo, using four specific aims: Aim-1 defines TED treatment for acute MGK in vivo by testing the hypothesis that increasing frequency and duration of TED application will potently treat acute MGK and blindness without significant side effects. Aim-2 establishes TED treatment for delayed-onset MGK in vivo by testing the hypothesis that low TED topical dosing for longer duration will effectively cure delayed-onset MGK without issues in rabbits. Aim-3 uncovers mechanisms used by TED in mitigating acute and delayed-onset MGK in vivo and in vitro. Aim-4 secures intellectual property rights, develops regulatory strategies, and advances TED topical ophthalmic drops as an antidote for SM-induced ocular injury towards human application. This will be accomplished using an established SM-vapor rabbit in vivo and human cornea organ culture ex vivo models, GMP-grade TED eye drops, and monitoring eyes in live rabbits in a time-dependent manner with clinical eye exams and diagnostic imaging. The characterization of mechanisms used by TED in mitigating MGK will be studied using corneal tissues collected after euthanasia by measuring integrity of corneal epithelial basement membrane, epithelial-stromal organization, and collagen fibril arrangement using qPCR, ELISAs, immunofluorescence, H&E, and transmission electron microscopy techniques utilizing our published methods. Successful completion of the project will lead to the development of an effective and safe therapy for acute and delayed MGK and medical countermeasure to minimize ocular obliteration caused by the accidental or intentional use of SM in humans, and therefore will have very high impact in field and public safety.

抽象的 自第一次世界大战以来，许多战争中都使用了一名囊泡和战士的硫磺芥末气（SM）。最多 最近在叙利亚。 SM迅速穿透了接触的眼睛，并通过伤害角膜组织而引起失明 组织和功能。在临床上，患者显示出一种称为芥末气的病理学，涉及 严重的眼部炎症，复发性上皮渗透，上皮细胞分离层流干细胞 缺乏，角膜溃疡，阴霾和新血管形成。 MGK病理生理学是双相，包括急性 并延迟发发，涉及多种机制。我们开发了一种小说，多模式的非甾体局部局部 眼科滴，涡轮眼滴（TED），包含4种FDA批准的仿制药，具有不同的模式 动作，在环境温度下稳定。我们的试点研究发现，局部TED有效治疗急性和 体内兔子和人角膜外体内的延迟发作的MGK没有明显的副作用。我们的中心 假设是，局部TED通过抑制SM诱导的早期抑制了体内急性和延迟发作的MGK 炎症反应，细胞外基质降解以及产生过多的纤维化和促疾病 血管生成因子没有明显的副作用。该项目测试了两个新的假设，以建立一个 使用四个特定目标：AIM-1 通过测试增加频率和持续时间的假设来定义体内急性MGK的TED处理 TED的应用将有效治疗急性MGK和失明，而不会显着副作用。 AIM-2建立 通过测试低TED局部剂量更长的假设，用于体内延迟发作的MGK的TED治疗 持续时间将有效治愈延迟发作的MGK，而不会在兔子中出现问题。 AIM-3发现使用的机制 在体内和体外减轻急性和延迟发作的MGK。 AIM-4确保知识产权， 制定监管策略，并进步TED局部眼科跌落作为SM诱导的解毒剂 对人类应用的眼部伤害。这将使用既定的sm-vapor兔子在体内实现 和人角膜器官培养物模型，GMP级TED眼滴和监视活兔子的眼睛 以时间依赖的方式进行临床眼科检查和诊断成像。表征 TED在缓解MGK中使用的机制将使用安乐死后收集的角膜组织进行研究 测量角膜上皮地下膜，上皮细胞组织和胶原原纤维的完整性 使用QPCR，ELISA，免疫荧光，H＆E和透射电子显微镜进行排列 利用我们已发表的方法的技术。成功完成该项目将导致发展 一种有效且安全的治疗，用于急性和延迟的MGK和医疗对策，以最大程度地减少眼镜 由人类意外或故意使用SM引起的遗嘱，因此会产生很高的影响 在现场和公共安全中。