Expansion of HSC for rescue in biodefense applications

描述（由申请人提供）：骨髓消融是由于放射或化学暴露导致的骨髓损伤，无论是治疗性的还是意外的，如果不治疗，会导致造血功能衰竭和死亡。在骨髓中，它是一种罕见的自我更新的造血干细胞（HSC），负责整个血液系统的生成和终身维持。造血细胞移植（HCT）被广泛应用于临床，使癌症患者能够在致命剂量的化疗和放疗中存活下来。因此，正是HSC重建了血液系统，并将HCT受者从致命的准备方案中拯救出来。正是HSC的这种能力，使它成为唯一有能力拯救那些暴露在致命剂量电离辐射下的细胞，这些电离辐射是由广泛的放射性或化学紧急情况造成的。在这种情况下，标准的HCT方案将无法在适当的时间范围或规模内适用，无法产生重大的医疗效益。在目前的环境中，由于恐怖主义或其他政治不稳定，辐射紧急情况的可能性越来越大，一种扩展人体造血干细胞的方法，可以储存起来以备将来使用，将对我们（国家）拯救暴露在这种辐射事件中的平民和军事人员的生命的能力产生不可思议的影响。该提案的目的是基于Cellerant专有的HSC扩增技术生产临床前系统。该技术需要通过腺病毒转导对纯化的HSC进行短暂修饰，以表达导致其体外扩增的基因。造血干细胞扩增后，通过冗余删除和选择程序去除非整合遗传物质，从而产生一种严格安全、有效且易于施用的治疗方法，用于暴露于危及生命的电离辐射或化学制剂剂量。

DESCRIPTION (provided by applicant): Myeloablation is the damage that occurs to the bone marrow as a result of radiological or chemical exposure whether therapeutically administered or accidental, that, if left untreated, results in hematopoietic failure and death. Within the bone marrow it is the rare population of self-renewing hematopoietic stem cells (HSC) that is responsible for the generation and lifelong maintenance of the entire blood system. Hematopoietic cell transplants (HCT) are widely used clinically to allow cancer patients to survive otherwise lethal doses of chemotherapy and radiation. Thus, it is the HSC that reconstitutes the blood system and rescues HCT recipients from the otherwise lethal preparative regimen. It is this ability of the HSC that also makes it the only cell capable of rescuing those exposed to lethal doses of ionizing radiation resulting from a widespread radiological or chemical emergency. In the case of such an event, standard HCT protocols would not be applicable in a suitable timeframe or scale to be of significant medical benefit. In the current environment of increasing potential of radiological emergencies due to terrorism or other political instabilities, a method of expanding human HSCs ex vivo that can be then be stored for future use, will have incredible impact on our (nation's) ability to save the lives of both civilians and military personnel exposed to such a radiological event. It is the aim of this proposal is to produce a pre-clinical system based on Cellerant's proprietary HSC expansion technology. This technology entails the transient modification of purified HSC by adenoviral transduction to express genes that result in their ex vivo expansion. After expansion of the HSCs, the nonintegrated genetic material is removed via redundant deletion and selection procedures to result in a rigorously safe, efficacious, and easily administered treatment for exposure to life-threatening doses of ionizing radiation or chemical agents.