TP508:A New Drug for Mitigating Lethal Effects of Radiation Exposure

描述（由申请人提供）：随着核爆风险的增加，需要有效的药物应对措施，可以在暴露后提供，以防止辐射引起的死亡。此外，当辐射合并损伤（RCI）时，死亡率显著增加。数千名受核爆炸伤害的人预计将死于被认为是亚致死的辐射暴露。因此，必须开发和储存减轻辐射和RCI影响的药剂，以备紧急使用。TP508 （rousalatide acetate）是一种新型多肽药物，目前正处于临床试验阶段，安全性和生产能力已得到证实，它通过减轻炎症、防止细胞凋亡、刺激一氧化氮（NO）的产生和逆转内皮功能障碍来刺激血管生成和组织修复。初步研究表明，TP508可减弱辐射诱导的细胞凋亡，逆转辐射诱导的内皮功能障碍，并促进受辐射大鼠的愈合。由于细胞凋亡、内皮功能障碍和愈合延迟与早期辐射损伤和随后导致死亡的影响有关，这些结果预测TP508治疗将在疾病过程的多个组织和多个点抵消辐射和RCI的致命影响。在本项目中，我们将使用伽玛辐照的C57BL/6小鼠来测试TP508作为辐射暴露和RCI对策的潜在功效。这个第一阶段项目的具体目标是：1)确定TP508应用于伤口或注射到小鼠体内是否会降低辐射或RCI导致的死亡率，以及这种治疗是否会加速这些小鼠的伤口愈合；2)确定TP508是否影响辐射和RCI的全身表现，包括细胞因子产生增加、细胞凋亡和内皮功能障碍。这些1期研究将确定TP508是否有潜力成为治疗辐射和rci引起的死亡的药物对策。如果TP508能降低辐射或RCI死亡率，将建议进行2期研究，以完成FDA的要求，启动临床试验，目标是获得政府许可和国家储备该药物以备紧急使用。

DESCRIPTION (provided by applicant): With increasing risk of nuclear detonation there is a need for effective medicinal counter-measures that can be delivered after exposure to prevent radiation-induced mortality. Adding to this need, mortality increases significantly when radiation is combined with injury (RCI). Thousands of people injured by nuclear detonation are expected to die from what was considered a sub-lethal radiation exposure. Therefore, agents to mitigate effects of radiation and RCI must be developed and stockpiled for emergency use. TP508 (rousalatide acetate), a novel peptide drug that is currently in clinical trials with established safety and manufacturing, stimulates angiogenesis and tissue repair by attenuating inflammation, preventing apoptosis, stimulating nitric oxide (NO) production, and reversing endothelial dysfunction. Preliminary studies suggest that TP508 attenuates radiation-induced apoptosis, reverses radiation-induced endothelial dysfunction, and stimulates healing in irradiated rats. Because apoptosis, endothelial dysfunction, and delayed healing are associated with early radiation damage and subsequent effects leading to mortality, these results predict that TP508 treatment will counteract lethal effects of radiation and RCI in multiple tissues and at multiple points in the disease process. In this project, we will use gamma irradiated C57BL/6 mice to test the potential efficacy of TP508 as a countermeasure for radiation exposure and RCI. Specific aims for this Phase 1 project will be: 1) to determine whether TP508 application to wounds or injection into mice reduces mortality due to radiation or RCI, and if this treatment accelerates wound healing in these mice; and 2) to determine whether TP508 affects systemic manifestations of radiation and RCI that include increased cytokine production, cellular apoptosis, and endothelial dysfunction. These Phase 1 studies will determine whether TP508 has potential to become a medicinal countermeasure for radiation and RCI-induced mortality. If TP508 reduces radiation or RCI mortality, Phase 2 studies will be proposed to complete FDA requirements to initiate clinical trials with a goal of government licensing and National Stockpiling of this drug for emergency use. PUBLIC HEALTH RELEVANCE: Following a nuclear detonation the combination of radiation and traumatic injury is expected to be much more deadly that radiation alone. TP508, a novel peptide drug with established manufacturing and safety, works through mechanisms thought to counteract effects of radiation. In this project, we will determine whether TP508 can prevent lethal effects of radiation and injury in irradiated animals as a first major step in development and potential FDA approval of TP508 as a drug to reduce the risk of death from radiation exposure.