Activated Protein C for Treatment of Radiation Combined Injury

描述(申请人提供)：本申请响应RFA-AI-07-038，并寻求支持评估重组激活蛋白C(APC)在治疗合并炎症和感染的放射损伤中的使用。APC已经在动物模型和人类患者中被证明可以降低脓毒症的死亡率，并被批准用于严重脓毒症的临床治疗。我们的初步数据支持这一观点，即APC在体内保护造血干细胞免受照射，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不同机械作用，包括：促进血管内皮细胞的存活和抗炎作用，以及对造血祖细胞的细胞保护/增殖作用。这些特性使已经获得FDA批准用于严重脓毒症的APC疗法成为治疗联合放射损伤的理想候选者。该应用程序的R21阶段将(1)在小鼠模型中提供原理证明，即APC在致命全身辐射照射后一次性输注可防止骨髓衰竭造成的死亡，此外还可防止致命全身辐射照射合并后续感染造成的死亡；(2)建立剂量方案以优化整体疗效，并延长APC的时间窗口，之后APC可在辐射照射后给予APC，但仍可防止死亡。R33阶段的研究将(1)探索是否可以通过使用具有选择性修饰生物活性的重组APC变体来进一步提高APC治疗的有效性和安全性；(2)证实人APC在移植到人类异种移植允许的NOG小鼠体内的人造血细胞辐射防护方面的体内有效性；以及(3)证明暴露后APC治疗在预防胃肠道损伤引起的死亡方面的潜在有效性。拟议的研究结果将为进一步探索APC的临床应用提供强有力的激励，并可能进一步探索更安全、疗效更好的重组APC变体，作为致命辐射暴露后的救命治疗。除了开发APC作为一种安全有效的辐射复合损伤对策外，这些研究有望获得的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。这项应用评估了重组形式的内源性活化蛋白C(APC)分子在治疗预防骨髓衰竭、感染和最终死亡方面的使用，因为它们可能发生在偶然的全身核辐射后。这项研究的结果预计将验证APC是一种安全有效的治疗核事故和其他涉及辐射暴露的威胁的受害者的方法。

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.