Development of Human, Autologous, Pluripotent Very Small Embryonic Like (VSELs) s

人类自体多能极小胚胎样 (VSEL) 的发育

• 批准号: 8436122
• 负责人: Denis Overend Rodgerson
• 金额: $ 30万
• 依托单位: CALADRIUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436122
• 关键词: Acute; Adult; Allogenic; Animal Model; Animals; Antigens; Autologous; Biological Products; Blood Component Removal; Blood Platelets; Bone Marrow; CD34 gene; Cancer Patient; Cause of Death; Cell Count; Cell Lineage; Cell Therapy; Cells; Cessation of life; Chimerism; Dependency; Development; Dose; Embryo; Event; Exposure to; Failure; Germ Cells; Goals; Grant; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Human Development; Immune; Immune system; In Vitro; Individual; Infection; Infectious Agent; Intervention; Leukocytes; Life; Lymphocyte; Measures; Methods; Mus; Myelogenous; Myocardial Infarction; Natural regeneration; Nuclear; Nuclear Accidents; Pancreas; Patients; Persons; Phase; Pluripotent Stem Cells; Population; Preclinical Testing; Procedures; Proliferating; Property; Radiation; Radiation Injuries; Radiation Syndromes; Radiation therapy; Recovery; Regimen; Resistance; Retina; Small Business Innovation Research Grant; Stem cell transplant; Stem cells; System; Tail; Technology; Testing; Time; Tissues; Transplantation; Vaccines; Veins; Virulence; Whole-Body Irradiation; cytokine; efficacy testing; graft vs host disease; healthy volunteer; irradiation; preclinical efficacy; reconstitution; repaired; response; stem cell therapy; whole body irradiation effect

DESCRIPTION (provided by applicant): In the event of a nuclear accident or terrorist bomb, large numbers of casualties will have been exposed to acute high-dose radiation. Those exposed will have compromised immune systems such that the virulence and infectivity of biological agents is dramatically increased. A compromised immune system exacerbates the effects of infectious agents and may preclude use of vaccines. Death can occur within 1-6 weeks following radiation exposure due to overwhelming infection or to massive bleeding. The primary cause of death from radiation injury is infection that is unrestrained due to the failure of the immune system. There is only one intervention that saves a fatally irradiated person - a rescue through stem cell transplantation. The cure rate for this treatment can be high, provided the treatment is delivered within 7-10 days following exposure to radiation. Our goal is to develop very small embryonic like stem cells (VSEL), which are autologous adult pluripotent stem cells, as a countermeasure to radiological and nuclear threat. The VSELs will be used to rescue the immune system of individuals suffering from the delayed effects of acute radiation syndrome (ARS). The cells are autologous and consequently when administered to a patient will not cause rejection or graft- versus host disease, a common cause of failure of allogeneic stem cell therapies. The cells are pluripotent and can be expanded and differentiated to all three germ cell lineages. In particular, VSELs can be differentiated to hemato/lymphopoietic lineage, and can rescue the immune system of mice exposed to lethal radiation. Furthermore, VSELs have been shown to repair damaged tissue in animal models of myocardial infarct and may also be effective in repairing other tissues including retina and pancreas. Consequently, VSELs might be an ideal cell therapy to regenerate the body's immune system and repair other tissues damaged by radiation exposure. Most importantly, VSELs are resistant to lethal irradiation, which destroys hematopoietic stem cells and most other stem cells in the body. Specifically, in mice exposed to lethal radiation, VSELs are alive in bone marrow and proliferate in response to the tissue damage caused by irradiation. Consequently, these cells represent a unique population of autologous PSCs that could be used to treat radiation exposure. Studies proposed in this grant will test whether irradiated VSELs, can rescue the immune system and prolong survival of irradiated mice. If successful, this finding would indicate that VSELs could be isolated from a person exposed to radiation and used to treat that same person. Furthermore, we will test whether human VSELs have the same curative effect as the murine VSELs and are able to reverse the loss of the hemato/lymphopoietic system resulting from whole body irradiation. Importantly, unlike the development of medicinal products which must undergo extensive preclinical testing before human trials, VSELs are autologous and may be more readily available for human testing once preclinical efficacy is established.

描述（由申请人提供）：如果发生核事故或恐怖炸弹，大量人员伤亡将暴露于急性高剂量辐射。暴露的人会损害免疫系统，从而大大增加了生物学剂的毒力和感染力。受损的免疫系统加剧了感染剂的作用，并可能排除使用疫苗的使用。由于压倒性感染或大量出血，可能在辐射暴露后的1-6周内发生死亡。辐射损伤导致死亡的主要原因是由于免疫系统失败而无情的感染。只有一种干预措施可以节省致命的人 - 通过干细胞移植进行营救。如果治疗在接触辐射后的7-10天内进行治疗，则治疗率可能很高。我们的目标是开发非常小的胚胎（VSEL）（VSEL），它们是自体多能干细胞，作为对放射学和核威胁的对策。 VSEL​​将用于营救患有急性辐射综合征（ARS）延迟作用的个体的免疫系统。这些细胞是自体的，因此，当给患者施用时，不会引起排斥或移植 - 宿主疾病，这是同种异体干细胞疗法失败的常见原因。细胞具有多能，可以扩展并区分到所有三个生殖细胞谱系。特别是，VSEL可以与血统/淋巴管谱系区分开，并可以挽救暴露于致命辐射的小鼠的免疫系统。此外，VSEL已被证明可以修复心肌梗塞动物模型中受损的组织，并且也可能有效地修复包括视网膜和胰腺在内的其他组织。因此，VSEL可能是一种理想的细胞疗法，可再生身体的免疫系统并修复因辐射暴露而损坏的其他组织。最重要的是，VSEL具有抗致命辐射，会破坏体内造血干细胞和大多数其他干细胞。具体而言，在暴露于致命辐射的小鼠中，VSEL在骨髓中还活着，并响应于辐射引起的组织损伤而增殖。因此，这些细胞代表了可用于治疗辐射暴露的独特自体PSC群体。该赠款中提出的研究将测试辐射的VSEL是否可以营救免疫系统并延长辐照小鼠的存活。如果成功，这一发现将表明VSEL可以与暴露于辐射的人中隔离，并用于治疗同一个人。此外，我们将测试人类VSEL是否具有与鼠VSEL相同的治疗作用，并能够逆转全身照射导致的血液/淋巴管系统的丧失。重要的是，与必须在人类试验之前进行广泛的临床前测试的药物的开发不同，VSEL是自体的，一旦建立了临床前疗效，可以更容易用于人类测试。