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

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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.