Extending the scope of PLX-R18 for H-ARS: efficacy in special populations and DEARE

摘要 涉及辐射的恐怖事件的威胁越来越大，以及发生辐射事故的可能性越来越大， 强调需要针对辐射采取有效的医学对策。造血系统 是对辐射最敏感的组织，导致造血急性辐射综合征(H-ARS)后 如果不治疗，高剂量辐射暴露会导致感染和/或出血死亡。H-ARS幸存者受苦 由于晚年受到急性辐射暴露(DEARE)的延迟影响，一些慢性病影响 多个器官系统。到目前为止，Neupogen(粒细胞集落刺激因子，G-CSF)和Neulasta (聚乙二醇化G-CSF)是FDA批准的唯一用于治疗H-ARS的MCM，将作为第一个- 针对暴露在高剂量辐射下的个人的直线治疗。这两个MCM或任何其他有效的H- 据我们所知，Ars MCM已经显示出对DeARE的疗效，尽管基于细胞的MCM尚未被 已评估。PLX-R18细胞是一种人类胎盘来源的细胞产物，已被证明显著 提高H-ARS动物模型的存活率，并正在开发FDA许可作为针对MCM的 辐射。鉴于PLX-R18在再灌流缺血模型中减少肾脏和心脏损伤的有效性，有 这些细胞在DeARE中也有疗效的理论基础。大多数测试H-ARS的MCM的研究都使用了 年轻的成年动物模型，但越来越清楚的是，对辐射和MCM的反应是年龄- 对成人有效的MCM可能对儿童或老年人无效。因此，MCM 对于H-ARS，也应该在儿科和老年动物模型中进行测试。大多数动物模型都是在 近亲繁殖的小鼠，类似于“同卵双胞胎”，因此是人类种群的糟糕模型。杰克逊 多样性近交(JDO)小鼠是现有的遗传多样性最强的小鼠，也是一种更相关的 人类。该项目的目标是将PLX-R18 H-ARS研究扩展到包括生存检查 对特殊群体(儿童和老年)和近交系小鼠的疗效以及PLX-R18缓解 死神在幸存者身上。我们还将研究与G-CSF的潜在相互作用。我们假设PLX-R18 符合理想的MCM的所有要求，并将在特殊情况下表现出显著的生存效率 种群和近交系小鼠，缓解H-ARS幸存者的DeARE的某些方面，不会相互作用 联合用药时G-CSF阴性。将追求以下具体目标：1)评估 PLX-R18在儿童和老年近交系小鼠模型和JDO小鼠中的存活效果，2)探索 幼年、儿童、老年和JDO小鼠PLX-R18细胞与G-CSF的相互作用 3)研究PLX-R18细胞减少DeARE的能力。 造血、肾脏和心血管系统。这一项目的成功完成将扩大 PLX-R18用于特殊人群和Deare，并将为特殊人群提供治疗选择 暴露在恶意或治疗性辐射中。

ABSTRACT The growing threat of terrorist events involving radiation, as well as the potential for radiation accidents, underscores the need for effective medical countermeasures (MCM) against radiation. The blood-forming system is the most sensitive tissue to radiation, resulting in the hematopoietic acute radiation syndrome (H-ARS) after high dose radiation exposures and death from infection and/or bleeding if untreated. Survivors of H-ARS suffer later in life by the delayed effects of acute radiation exposure (DEARE), a number of chronic illnesses affecting multiple organ systems. To date, Neupogen (granulocyte-colony stimulating factor, G-CSF) and Neulasta (pegylated-G-CSF) are the only MCM approved by the FDA for treatment of H-ARS, and will be given as first- line treatments for individuals exposed to high dose radiation. Neither of these MCM, nor any other effective H- ARS MCM to our knowledge, have shown efficacy for DEARE, although cell-based MCM have not yet been evaluated. PLX-R18 cells are a human placental-derived cell product that have been shown to significantly increase survival in H-ARS animal models, and is under development for FDA licensure as a MCM against radiation. Given the efficacy of PLX-R18 to reduce kidney and heart injury in re-perfusion ischemia models, there is rationale that these cells may have efficacy in DEARE also. Most studies testing MCM for H-ARS have used young adult animal models but it is becoming increasingly clear that responses to radiation and MCM are age- dependent, and that MCM that are effective in adults may not be effective in children or the elderly. Thus, MCM for H-ARS should also be tested in pediatric and geriatric animal models. Most animal models are developed in inbred mice, which are similar to “identical twins” and thus poor models of the human population. Jackson Diversity Outbred (JDO) mice are the most genetically diverse mice available and a more relevant model of humans. The goal of this project is to extend the PLX-R18 H-ARS studies to include examination of survival efficacy in special populations (pediatric an geriatric) and outbred mice, and the ability of PLX-R18 to alleviate DEARE in survivors. We will also examine potential interactions with G-CSF. We hypothesize that PLX-R18 fulfills all the requirements of an ideal MCM and will demonstrate significant survival efficacy in special populations and outbred mice, alleviate some aspects of DEARE in H-ARS survivors, and will not interact negatively with G-CSF when co-administered. The following specific aims will be pursued: 1) evaluate the survival efficacy of PLX-R18 in pediatric and geriatric inbred mouse models and in the JDO mice, 2) explore the interaction of PLX-R18 cells with G-CSF in young adult, pediatric, geriatric, and JDO mice and determine mechanisms of survival efficacy, and 3) investigate the ability of PLX-R18 cells to reduce DEARE in hematopoietic, renal, and cardiovascular systems. Successful completion of this project will extend the scope of PLX-R18 to special populations and in DEARE, and will provide treatment options for special populations exposed to malicious or therapeutic radiation.