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

项目摘要摘要 硫磺芥末(SM)、氮芥末(NM)和路易氏剂(LOW)是发泡剂中含量最高的 威力巨大的化学武器，是当前制定对策的重点。在过去，缺乏 NM、SM和LEW诱导的眼损伤模型的毒性和治疗机制研究 靶向一直是开发有效疗法的主要障碍。然而，近年来，我们已经 成功开发并鉴定了所有三种发泡剂(NM、SM和LOW)诱导的眼(角膜) 兔体内损伤模型，与人类相关。此外，我们还发现COX-2和 诱导型一氧化氮合酶、血管内皮生长因子和基质金属蛋白酶-9可能作为炎症、新生血管和微血管形成的介质。 分别在这三种发泡剂造成的眼部损伤中。这是一个重要的发现，因为它表明 对这些发泡剂中的一种所引起的眼损伤有效的药剂也将对 其他。事实上，在我们的概念验证疗效研究中，我们证明了地塞米松(DEX，AN FDA批准的药物)是改善所有三种发泡剂(NM、SM、LEW)诱导的有效药物 兔眼活体损伤的实验研究。这是一项重要的发现，因为这种新用途的调控途径 由于DEX的新使用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，从而减少应用程序所需的数据 更容易获得批准的途径。根据CU技术转移办公室的审查，DEX的一个优势是 将这种新用途推向市场不存在竞争性知识产权(IP)障碍。越远 使用DEX的好处是，我们不需要生成额外的IP来创建商业 由于DEX作为非专利和品牌处方药可从多种来源以低成本获得， 在医疗紧急情况下不会出现短缺。一起，基于我们完成的研究和 明确未来的调控途径，我们的假设是DEX具有很强的逆转这两种情况的潜力 芥子气和砷所致的眼损伤，以及作为一种有前景的靶向“优化线索”。 治疗，它可以很容易地在医疗紧急情况下供人类使用。我们的具体目标是：1) 优化地塞米松治疗泡沫剂所致兔眼损伤的给药频率；2)评价 对抗起泡剂诱导的人角膜损伤最有效的地塞米松治疗方案 角膜器官培养；3)明确地塞米松解救水泡剂所致眼球损伤的分子机制 伤害；以及4)制定和遵循监管战略，批准DEX适应症作为有效的 发泡剂致眼损伤的防治对策。我们的目标有望完成 使地塞米松为下一阶段的先进药物开发过程做好准备，为 FDA批准作为一种有效的抢救药物，用于治疗发泡剂引起的眼部损伤。

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.