Developing a bank of purified myeloid progenitor cells as a bridging therapy for transient pancytopenia resulting from radiation injury

开发纯化的骨髓祖细胞库作为放射损伤引起的短暂性全血细胞减少症的桥接疗法

• 批准号: 10081134
• 负责人: Brian H. Johnstone
• 金额: $ 30万
• 依托单位: OSSIUM HEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-18 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081134
• 关键词: Ablation; Address; Agreement; Allogenic; Animals; Antibodies; Antibody-drug conjugates; Area; Biological Assay; Blood; Blood Platelets; Bone Marrow; Bone Marrow Purging; Businesses; CD34 gene; Cancer Patient; Caring; Cell Separation; Cell Therapy; Cell surface; Cells; Cellular Structures; Cessation of life; Clinical; Colony-Forming Units Assay; Complement; Cryopreservation; Cyclic GMP; Devices; Dose-Rate; Engraftment; Ensure; Evaluation; Event; Exposure to; FDA approved; Flow Cytometry; Funding; Future; HLA Antigens; Health; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhage; Ice; In Vitro; Individual; Infection; Infection prevention; Infectious Agent; Injury; Intervention; Ionizing radiation; Lead; Leukopenia; Licensure; Major Histocompatibility Complex; Medical; Modeling; Mus; Myeloid Progenitor Cells; National Institute of Allergy and Infectious Disease; Natural Immunity; Neutropenia; New York City; Nuclear; Nuclear Warfare; Organ Donor; Organ Procurements; Pancytopenia; Patients; Pharmaceutical Preparations; Phase; Population; Procedures; Process; Production; Proto-Oncogene Protein c-kit; Qualifying; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Protection; Radiation Toxicity; Radiation exposure; Radiation therapy; Reagent; Recombinant Cytokines; Regimen; Registries; Reporting; Research; Risk; Safety; Ships; Source; Supportive care; System; T-Lymphocyte; Technology; Testing; Thrombocytopenia; Tissue Donations; Transplantation; Treatment Protocols; Washington; Wood material; Work; Xenograft procedure; animal rule; base; biodosimetry; bone; cell bank; conditioning; cost; cytokine; cytotoxic; graft vs host disease; hematopoietic cell transplantation; high risk; in vivo; infection risk; mass casualty; medical countermeasure; metropolitan; neutrophil; novel; optimal treatments; phase 1 study; pre-clinical; prevent; process optimization; programs; radiation effect; reconstitution; scale up; stem cells; success

ABSTRACT Exposure to even moderate levels (<3 Gy) of ionizing radiation can result in severe pancyotopenia, placing patients as wells as victims of accidental exposure at high risks for infection and uncontrolled hemorrhaging. Accidental exposure differs from radiation therapy in that biodosimetry (e.g., type of radiation, dose and dose rate) is often uncertain; consequently, the optimal treatment regimen to ameliorate the effects of radiation is not immediately evident. Therefore, victims of accidental ionizing radiation exposure would benefit from bridging therapies to traverse extended periods of neutropenia and thrombocytopenia until the optimal course of medical care can be determined. Ossium Health proposes to develop a bank of myeloid progenitor cells (MPC) from deceased donor bone marrow (BM). The strategy employs commercially available immunomagnetic selection reagents and clinical-scale closed-system semi-automated devices to specific select MPC from whole BM based on defining cell surface markers CD34+CD38+. The proposed Phase I studies build on our previous success with selecting large numbers (>150 million) of stem and progenitor cells from organ donor BM. We will evaluate combinations of selection, depletion and ablation to purify MPC without contaminating T cells long-term repopulating stem cells to prevent graft versus host disease. The cells will be validated in vitro and in vivo in a mouse xenotransplantation study to evaluate reestablishment of short-term innate immunity. The overall product of this research program will be a compelling preclinical package to justify definitive studies to support FDA approval under the Animal Rule for a novel radiation/nuclear mass casualty medical countermeasure bridging therapy. Future commercial viability for both medical countermeasures and civilian uses is enhanced by the up to 5-fold lower cost for manufacturing compared to current technologies.

抽象的 即使暴露于中等水平（<3 Gy）的电离辐射也可能导致严重的 全血细胞减少症，使患者以及意外接触的受害者处于高风险中 感染和不受控制的出血。意外暴露与放射治疗的不同之处在于 生物剂量测定（例如辐射类型、剂量和剂量率）通常是不确定的；最后， 改善辐射影响的最佳治疗方案尚未立即显现出来。 因此，意外电离辐射暴露的受害者将受益于桥接 治疗以克服长时间的中性粒细胞减少症和血小板减少症，直到达到最佳状态 可以确定医疗护理过程。 Ossium Health 提议开发死者骨髓祖细胞 (MPC) 库 供体骨髓 (BM)。该策略采用市售的免疫磁性 选择试剂和临床规模的封闭系统半自动化设备来具体选择 基于定义细胞表面标记 CD34+CD38+ 的来自整个 BM 的 MPC。拟议的 第一阶段研究建立在我们之前成功选择大量（>1.5 亿） 来自器官供体 BM 的干细胞和祖细胞。我们将评估选择的组合， 耗尽和消融纯化 MPC，而不污染 T 细胞长期再生干细胞 细胞来预防移植物抗宿主病。这些细胞将在体外和体内进行验证 小鼠异种移植研究评估短期先天免疫的重建。 该研究计划的总体产品将是一个令人信服的临床前方案，以证明其合理性 明确的研究支持 FDA 根据动物规则批准新型辐射/核 大规模伤亡医疗对策桥接治疗。双方未来的商业可行性 医疗对策和民用用途因成本降低多达 5 倍而得到增强 与现有技术相比的制造。