OssioStem-matched multipotent MSC (M3): banked, low passage bone marrow MSC for treatment of hematopoietic acute radiation syndrome.

摘要 急性放射综合征（H-ARS）的造血亚综合征是由甚至 中度暴露于电离辐射，这对造血干细胞（HSC）是致命的， 骨髓（BM）。造血干细胞移植（HSCT）是一种潜在的挽救生命 H-ARS受害者的治疗;然而，由于通常不推荐， 移植物抗宿主病的相关并发症。最近的临床试验，包括我们的 合作者，已经证明间充质基质/干细胞（MSC）输注 预防/治疗移植物抗宿主病（GVHD）并减少HSCT后的移植物衰竭。 MSC的这些有益效果是由于细胞的有效免疫调节特性。 此外，MSC具有许多其他治疗特性，显示出改善病理 与影响胃肠道系统、皮肤和肝脏的其他ARS综合征相关。因此，在本发明中， MSC具有治疗与电离辐射相关的各种病理的潜力。 辐射暴露 Ossium Health正在开发一种独特的BM衍生多能MSC来源， 已故器官捐献者这种细胞疗法，称为OssioStem-M3（匹配多能 MSC）与其他MSC来源相比具有明显的优势，因为它与来源 对于从相同供体获得的HSCT移植物（OssioStem-HSC）。此外，大 可以从死亡供体获得的BM体积产生异常高的数量， MSc.这一点很重要，因为MSC支持HSCT的功效与以下因素呈负相关： 因此，低传代OssioStem-M3上级获得的“第三方”MSC 必须通过许多通道来放大。 我们在这里建议优化分离OssioStem-M3的方法， 描述其物理特性和生物功能。我们亦建议 在H-ARS的大型（猪）和小型（小鼠）模型中证明了有效性。最后我们将 构建和测试下一代设备，以提高 OssioStem-HSC生产。 这项研究计划的整体产品将是一个强大的生产过程和一个 令人信服的临床前包装，以证明确定性研究的合理性，以支持FDA批准H-ARS 根据动物规则。

ABSTRACT The hematopoietic subsyndrome of acute radiation syndrome (H-ARS) is induced with even moderate exposure to ionizing radiation, which is lethal to hematopoietic stem cells (HSC) in the bone marrow (BM). Hematopoietic stem cell transplant (HSCT) is a potential life-saving treatment for H-ARS victims; however, it is not generally recommended due to commonly associated complication of graft-versus-host disease. Recent clinical trials, including that of our collaborator, have demonstrated that mesenchymal stromal/stem cell (MSC) infusions prevent/treat graft-versus-host-disease (GVHD) and reduce graft failure following HSCT. These salutary effects of MSC are due to potent immunomodulatory properties of the cells. Furthermore, MSC possess many other therapeutic properties shown to ameliorate pathologies associated with other ARS syndromes effecting the gastrointestinal system, skin and liver. Thus, MSC have the potential to treat the full spectrum of pathologies associated with ionizing radiation exposure. Ossium Health is developing a unique source of BM-derived multipotent MSC obtained from deceased organ donors. This cellular therapy, termed OssioStem-M3 (matched multipotent MSC) has a distinct advantage over other MSC sources in that it is donor-matched to a source for HSCT grafts (OssioStem-HSC) obtained from the same donors. Additionally, the large volumes of BM that can be obtained from a deceased donor yield exceptionally high numbers of MSC. This is important given that efficacy of MSC for supporting HSCT is negatively related to passage number; thus, low passage OssioStem-M3 is superior to “third party” MSC obtained from living donors which must be amplified through many passages. We propose here to optimize methods for isolation of OssioStem-M3 and thoroughly characterize their physical characteristics and biological function. We also propose to demonstrate efficacy in large (porcine) and small (mouse) models of H-ARS. Finally, we will build and test next generation devices for increasing the consistency and throughput of OssioStem-HSC production. The overall product of this research program will be a robust production process and a compelling preclinical package to justify definitive studies to support FDA approval for H-ARS under the Animal Rule.