Activated Protein C for Treatment of Radiation Combined Injury

描述（由申请人提供）：本申请响应RFA-AI-07-038，并寻求对评价重组活化蛋白C（APC）在治疗放射损伤合并炎症和感染中的用途的支持。APC已被证明可以降低动物模型和人类患者的脓毒症死亡率，并被批准用于治疗严重脓毒症的临床用途。我们的初步数据支持APC保护造血干细胞免受体内照射的概念，从而降低全身照射后的死亡率，可能是通过对多个器官系统的机械性不同作用，包括：对血管内皮细胞的存活促进和抗炎作用以及对造血祖细胞的细胞保护/增殖作用。这些特性使得APC疗法成为治疗联合放射损伤的理想候选者，APC疗法已经被FDA批准用于严重脓毒症。本申请的R21阶段将（1）在小鼠模型中提供原理证明，即在致死性全身辐射暴露后作为单次推注输注施用的APC可以预防来自骨髓衰竭的致死性，以及由致死性全身辐射暴露复合随后的感染引起的致死性;和（2）建立一种给药方案以优化总体功效并扩大时间窗，在该时间窗之后，可以在辐射暴露后给予APC并仍然防止死亡。该研究的R33阶段将（1）探索是否可以通过使用具有选择性修饰的生物活性的重组APC变体来进一步改善APC疗法的功效和安全性，（2）产生人APC在移植到人异种移植物允许的NOG小鼠中的人造血细胞的辐射保护中的体内功效的证据;和（3）产生暴露后APC治疗在预防胃肠道损伤引起的死亡中的潜在功效的证据。拟议研究的结果将为进一步探索APC的临床用途提供强有力的激励，以及可能更安全的具有改善疗效的重组APC变体，作为致命辐射暴露后的救生治疗。除了发展APC作为一种安全有效的对抗辐射联合损伤的对策外，这些研究的预期见解将为研究天然蛋白C抗凝途径与保护造血系统免受辐射损伤之间的这种全新联系的细胞和分子基础奠定坚实的基础。本申请评价了内源性活化蛋白C（APC）分子重组形式用于治疗性预防骨髓衰竭、感染和最终死亡的用途，因为它们可能在偶然的全身暴露于核辐射后发生。预计研究结果将验证APC作为核事故和其他辐射威胁受害者的安全有效治疗方法。

DESCRIPTION (provided by applicant): This application responds to RFA-AI-07-038 and seeks support for evaluating the use of the recombinant activated protein C (APC) in the treatment of radiation injury combined with inflammation and infection. APC has been already shown to reduce sepsis mortality in animal models and in human patients, and is approved for clinical use in the treatment of severe sepsis. Our preliminary data support the notion that APC protects hematopoietic stem cells from irradiation in vivo and thereby reduces mortality after whole body irradiation, possibly via mechanistically diverse effects on multiple organ systems, including: survival-promoting and anti-inflammatory effects on vascular endothelium and cytoprotective/proliferative effects on hematopoietic progenitors. These properties make APC therapy, which is already FDA approved for severe sepsis, an ideal candidate for the treatment of combined radiation injury. The R21 phase of this application will (1) provide proof-of-principle in a mouse model that APC administered as a single bolus infusion after lethal whole body radiation exposure can prevent lethality from bone marrow failure, in addition to lethality caused by lethal whole body radiation exposure compounded by subsequent infection; and (2) establish a dosing regimen to optimize overall efficacy and to expand the time window after which APC can be given following radiation exposure and still prevent mortality. The R33 phase of the study will (1) explore whether efficacy and safety of APC therapy can be further improved by the use of recombinant APC variants with selectively modified bioactivities, (2) generate evidence for the in vivo efficacy of human APC in the radioprotection of human hematopoietic cells transplanted into human xenograft-permissive NOG mice; and (3) generate evidence for the potential efficacy of post-exposure APC therapy in preventing death caused by gastrointestinal injury. Outcomes of the proposed studies will provide a strong incentive to further explore the clinical use of APC, and possibly safer recombinant APC variants with improved efficacy, as a life-saving treatment after lethal radiation exposure. In addition to developing APC as a safe and effective countermeasure against radiation combined injury, insights expected from these studies will lay a solid foundation for investigating the cellular and molecular basis of this entirely novel connection between the natural protein C anticoagulant pathway and protection of the hematopoietic system against radiation injury. This application evaluates the use of recombinant forms of the endogenous activated protein C (APC) molecule for the therapeutic prevention of bone marrow failure, infection, and ultimately mortality as they may occur after incidental whole body exposure to nuclear radiation. Outcomes of the study are expected to validate APC as a safe and effective treatment for victims of nuclear accidents and other threats involving radiation exposure.