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

资助父母奖摘要 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)是一种潜在的挽救生命的疗法 对于H-ARS患者；但是，通常不建议使用，因为通常 移植物抗宿主病的并发症。最近的临床试验，包括我们的合作者的试验， 已证明间充质基质/干细胞(MSC)输注预防/治疗移植物- 抗宿主病(GVHD)和减少HSCT后移植失败。 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辐射相关的全光谱病理。 曝光。 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来源相比有一个明显的优势，因为它是供体匹配的HSCT来源 移植物(OssioStem-HSC)取自相同的供者。此外，BM的大容量 这可以从已故捐赠者获得异常高数量的MSC。这是 重要的是，骨髓间充质干细胞支持造血干细胞移植的效果与传代呈负相关 因此，低传代的OssioStem-M3要优于从活体中获得的“第三方”MSC 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，我们将建立 并测试下一代设备，以提高OssioStem的一致性和吞吐量- 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》。 供补充的摘要 要求追加资金，以弥补因不得不将 原研究地点(Altasciences)停止后在新研究地点进行的猪H-ARS研究 程序。这些资金将用于弥补猪H-ARS研究的预算缺口和 添加控制臂。所要求的补充金额是基于CRL提供的报价 2020年9月11日(引用编号CRL272922)。4个研究组的报价金额 是389,580美元。列入额外的可选组织病理学费用(39800美元)， 这项研究的总费用为429,380美元(即389,580美元+39,800美元)。备注 组织病理学费用是原始报价的一部分，但在考虑中被删除了 达到这项研究的最初预算数额。因此，关于补充的请求 CRL的研究费用为115,380美元，这是429,380美元和324,000美元之间的差额。

Abstract of funded parent award 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. Abstract for supplement Supplemental funds are requested to cover a budget deficit caused by having to place the porcine H-ARS study at a new study site after the original site (Altasciences) discontinued their program. These funds will be used to cover the porcine H-ARS study budgetary shortfall and add a control arm. The supplemental amount requested is based on a quote provided by CRL on September 11, 2020 (quote number CRL272922). The amount quoted for 4 study groups was $389,580. With the inclusion of the additional of optional histopathology costs ($39,800), the total cost for the study was brought to $429,380 (ie., the sum of $389,580 + $39,800). Note that the histopathology costs were part of the original quote but were removed in consideration of meeting the originally budgeted amount for the study. Thus, the request for supplementing the CRL study is $115,380 which is the difference between $429,380 and $324,000.