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性或化学暴露（无论是治疗性给药还是意外）导致的骨髓损伤，如果不进行治疗，将导致造血功能衰竭和死亡。在骨髓中，它是罕见的自我更新造血干细胞（HSC）群体，负责整个血液系统的生成和终身维护。造血细胞移植（HCT）在临床上被广泛使用，以使癌症患者在致命剂量的化疗和放疗中存活。因此，HSC重建血液系统并将HCT接受者从其他致命的准备方案中拯救出来。HSC的这种能力也使其成为唯一能够拯救那些因广泛的辐射或化学紧急情况而暴露于致命剂量电离辐射的人的细胞。在此类事件的情况下，标准HCT方案将不适用于具有显著医疗获益的适当时间范围或规模。在当前由于恐怖主义或其他政治不稳定性而增加辐射紧急情况的可能性的环境中，一种体外扩增人HSC的方法，然后可以储存以供将来使用，将对我们（国家）拯救暴露于这种辐射事件的平民和军事人员的生命的能力产生难以置信的影响。该提案的目的是生产一种基于Cellerant专有HSC扩增技术的临床前系统。该技术需要通过腺病毒转导对纯化的HSC进行瞬时修饰以表达导致其离体扩增的基因。在HSC扩增后，通过冗余删除和选择程序去除非整合的遗传物质，以产生严格安全、有效且易于施用的暴露于危及生命剂量的电离辐射或化学试剂的治疗。

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.