Optimization of AEOL10150 treatment of sulfur mustard-induced lung toxidrome in a pig model

我们的长期目标是开发催化抗氧化剂AEOL10150作为硫磺的医学对策 芥子气致急性肺损伤。硫磺芥子气是一种常用的化学战剂。 它已经部署在军事人员和平民身上，造成了大量伤亡。目前 目前还没有有效的治疗硫芥子气暴露的方法。AEOL10150独一无二地针对反应性 与烷基化产生的细胞和组织损伤有关的氧和氮物种 以及硫磺和氮素芥菜等试剂。我们之前已经证明，AEOL10150可以保护 肺对几种化学物质的暴露，包括氯、光气、梭曼和硫芥子气 在啮齿动物模型中。AEOL10150是一种晚期开发的放射性肺损伤缓释剂，通过 风神制药。AEOL10150处于高级药物开发阶段，具有完整的GLP慢性安全性 对小鼠和猴子的研究，完成化学、制造和控制(CMC)，以及阶段1A 人体临床安全性试验。这项UO1拨款的目的是优化AEOL10150的剂量和在 作为FDA动物规则要求的一部分，SM诱导的猪急性肺损伤模型。我们会 通过3个具体目标来实现这一目标。第一个目标是建立猪硫芥末吸入模型。 这会在24至48小时内造成急性呼吸道损伤和死亡。第二个目标是优化 AEOL10150在猪硫芥末吸入模型中的药效学。第三个目标将决定 AEOL10150在SM诱导的猪急性肺损伤模型中的疗效，同时降低死亡率。这些 研究将使AEOL10150向前发展，并帮助设计所需的关键安全性和有效性研究 申请FDA根据动物规则对AEOL10150进行监管批准。AEOL10150有可能成为一个广泛的 针对传统化学战剂和有毒工业化学品的光谱医学反抗剂 造成肺部毒素沉着。

Our long term goal is to develop the catalytic antioxidant AEOL10150 as medical countermeasure for sulfur mustard gas-induced acute lung injury. Sulfur mustard gas is a commonly stockpiled chemical warfare agent that has been deployed on military personnel and in civilian populations producing mass casualties. Currently there are no effective treatments for sulfur mustard gas exposure. AEOL10150 uniquely targets reactive oxygen and nitrogen species that have been implicated in cellular and tissue damage produced by alkylating agents such and sulfur and nitrogen mustards. We have previously shown that AEOL10150 can protect the lung against several chemical agent exposures including chlorine, phosgene, soman, and sulfur mustard gases in rodent models. AEOL10150 is in advanced development as a mitigator of radiation-induced lung injury by Aeolus Pharmaceuticals. AEOL10150 is in advanced drug development with completed GLP chronic safety studies in mice and monkeys, completed Chemistry, Manufacturing, and Control (CMC), and a phase 1A clinical safety trials in humans. The purpose of this UO1 grant is to optimize AEOL10150 dose and delivery in a swine model of SM-induced acute lung injury as part of the requirements of the FDA Animal Rule. We will achieve this goal through 3 specific aims. The first aim will establish a swine sulfur mustard inhalation model that produces acute respiratory injury and mortality within 24 to 48 hours. The second aim will optimize AEOL10150 pharmacodynamics in the swine sulfur mustard inhalation model. And the third aim will determine the efficacy of AEOL10150 in a swine model of SM-induced acute lung injury while mitigating mortality. These studies will allow AEOL10150 to move forward and help design the pivotal safety and efficacy studies needed for regulatory FDA approval of AEOL10150 under the animal rule. AEOL10150 has the potential to be a broad spectrum medical counteragent against traditional chemical warfare agents and toxic industrial chemicals that inflict a lung toxidrome.