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

摘要 EVEN诱导急性放射综合征造血亚综合征(H-ARS) 适度暴露于电离辐射，这对中国人的造血干细胞(HSC)是致命的 骨髓(BM)。造血干细胞移植(HSCT)是一种潜在的救命手段 对H-ARS患者的治疗；然而，由于通常 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，已经证明了间充质基质/干细胞(MSC)输注 预防/治疗移植物抗宿主病(GVHD)，减少HSCT后移植物衰竭。 MSC的这些有益作用是由于细胞具有强大的免疫调节特性。 此外，骨髓间充质干细胞还具有许多其他治疗特性，可改善病理。 与影响胃肠道系统、皮肤和肝脏的其他ARS综合征有关。因此， 骨髓间充质干细胞有可能治疗与电离相关的全光谱病理。 辐射暴露。 铯健康公司正在开发一种独特的BM来源的多潜能MSC，该来源来自 已故的器官捐赠者。这种细胞疗法被称为OssioStem-M3(匹配的多潜能 MSC)与其他MSC源相比有一个明显的优势，因为它是供体匹配的源 移植自相同供者的干细胞移植(OssioStem-HSC)。此外，大型 从已故捐赠者身上获得的骨髓体积非常高， MSC.这一点很重要，因为MSC对支持HSCT的有效性与 传代数；因此，低传代的OssioStem-M3优于获得的“第三方”MSC 来自活着的捐赠者，必须通过许多途径加以放大。 我们建议优化OssioStem-M3的分离方法，并彻底 描述它们的物理特征和生物功能。我们还建议 在H-ARS的大(猪)和小(鼠)模型上展示有效性。最后，我们会 构建和测试新一代设备，以提高 OssioStem-HSC生产。 这项研究计划的总体产品将是一个稳健的生产过程和一个 令人信服的临床前一揽子计划证明最终研究是合理的，以支持FDA批准H-ARS 根据《动物法则》。

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.