Dexamethasone as an Effective Therapy for Ocular Injuries by Vesicating Agents.

项目摘要 硫芥子气（SM）、氮芥子气（NM）和路易石（LEW）是最常见的起泡剂 强大的化学武器，是目前制定对策的重点。过去，缺乏 NM-、SM-和LEW-诱导的眼损伤模型，以鉴定毒性和治疗性眼损伤的机制。 目标一直是开发有效疗法的主要障碍。然而，近年来，我们 成功开发并表征了所有三种囊泡剂（NM、SM和LEW）诱导的眼部（角膜） 兔体内损伤模型，与人类相关。此外，我们还发现了考克斯-2表达的增加， iNOS、VEGF和MMP-9作为炎症、新生血管形成（NV）和微泡形成的可能介质， 分别用于这三种水疱剂引起的眼部损伤。这是一个重要的发现，因为它表明， 有效对抗由这些起疱剂之一诱导的眼损伤的药剂也将有效对抗 他人事实上，在我们的概念疗效研究中，我们证明了地塞米松（DEX，一种 FDA批准的药物）是改善所有三种水疱剂（NM，SM，LEW）诱导的 在兔体内的眼损伤。这是一个重要的发现，因为这种新用途的监管途径 DEX的应用程序更容易实现，因为DEX的新用途应用程序将能够依赖于现有的 参考DEX应用程序的安全性和有效性数据，导致应用程序所需的数据减少， 更容易的审批途径。根据CU技术转让办公室的审查，DEX的一个优势是 没有竞争性知识产权（IP）障碍将这种新用途推向市场。进一步 使用DEX的优点是，我们不需要生成额外的IP来创建商业广告 产品，因为DEX作为一种仿制药和品牌处方药可以从多种来源以低成本获得， 并且在医疗紧急情况下不会出现短缺。根据我们完成的研究， 明确的调控途径，我们的假设是，DEX有很强的潜力，以扭转这两个 芥子气和砷引起的眼损伤，并作为一个有前途的有针对性的“优化铅” 治疗，它可以很容易地供人类使用的医疗紧急情况。我们的具体目标是：1） 优化DEX的给药频率以治疗发泡剂诱导的兔体内眼损伤; 2）评估 对抗起疱剂诱导的人类角膜损伤的最有效DEX治疗方案 角膜器官培养; 3）阐明DEX拯救水泡剂诱导的眼内炎性细胞的分子机制 损伤;以及4）制定和遵循监管策略，以批准DEX适应症作为有效的 水泡剂致眼损伤的对策我们的目标的完成预计将 使地塞米松为下一阶段的先进药物开发过程做好准备， FDA批准作为一种有效的抢救药物，用于治疗水泡药引起的眼损伤。

Project Summary Abstract Sulfur mustard (SM), nitrogen mustard (NM) and lewisite (LEW) are vesicating agents that are among the most potent chemical weapons, and are the current focus for the development of countermeasures. In the past, lack of NM-, SM- and LEW-induced ocular injury models to identify the mechanisms of toxicity and therapeutic targets has been a major impediment to developing effective therapies. However, in recent years, we have successfully developed and characterized all three vesicants (NM, SM, and LEW)-induced ocular (corneal) injury models in vivo in rabbits, relevant to humans. Also, we identified an increased expression of COX-2 and iNOS, VEGF, and MMP-9 as possible mediators of inflammation, neovascularization (NV) and microvesication, respectively, in ocular injuries by these three vesicants. This is an important finding as it suggests that an agent effective against the ocular injury induced by one of these vesicants would also be effective against the others. Indeed, in our proof of concept efficacy studies, we demonstrated that dexamethasone (DEX, an FDA approved drug) is an effective agent in ameliorating all three vesicants (NM, SM, LEW)-induced ocular injuries in vivo in rabbits. This is a significant finding because the regulatory pathway for this new use of DEX is much easier to pursue, since the new use application for DEX would be able to rely on the existing safety and efficacy data of the reference DEX application, leading to less data needed for the application and an easier approval pathway. An advantage of DEX, based on review by the CU technology transfer office, is that there are no competitive intellectual property (IP) barriers to bringing this new use to market. The further advantage of using DEX is that we do not need to generate additional IP in order to create a commercial product, as DEX is available at a low cost from multiple sources as a generic and branded prescription drug, and will have no shortages in times of a medical emergency. Together, based on our completed studies and clear regulatory pathway forward, our hypothesis is that DEX has strong potential to reverse both mustard- and arsenical-induced ocular injury, and that as a promising targeted `optimized lead' therapeutic, it can be easily available for human use in medical emergency. Our specific aims are to: 1) optimize dosing frequency of DEX to treat vesicating agents-induced in vivo ocular injury in rabbits; 2) evaluate the most effective DEX treatment regimen to counteract vesicating agents-induced corneal injury in human corneal organ culture; 3) define the molecular mechanism of DEX in rescuing vesicating agents-induced ocular injury; and 4) develop and follow regulatory strategies for approval of DEX indication as an effective countermeasure against vesicating agent-induced ocular injury. Completion of our aims is anticipated to make dexamethasone ready for next stage of advanced drug development process with a clear path for FDA approval as an effective rescue medication for vesicants-induced ocular injuries.