Expansion of HSC for rescue in biodefense applications

描述(由申请人提供)：骨髓消融术是由于放射或化学暴露而对骨髓造成的损害，无论是治疗性的还是意外的，如果不进行治疗，会导致造血衰竭和死亡。在骨髓中，负责整个血液系统的生成和终生维持的是罕见的自我更新的造血干细胞(HSC)群体。造血细胞移植(HCT)被广泛用于临床，以使癌症患者在其他致命剂量的化疗和放射治疗中存活下来。因此，正是HSC重建了血液系统，并将接受HCT的人从原本致命的准备方案中解救出来。正是HSC的这种能力，也使其成为唯一能够拯救那些因大范围的放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。在这种情况下，标准的HCT方案将不能在适当的时间范围或规模内适用，从而产生重大的医疗效益。在当前由于恐怖主义或其他政治不稳定而可能出现越来越多的辐射紧急情况的环境下，一种在体内扩大人类造血干细胞并随后可以储存以供未来使用的方法，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令人难以置信的影响。这项提案的目的是基于Cellerant的专有HSC扩展技术生产一种临床前系统。这项技术需要对腺病毒转导纯化的HSC进行瞬时修饰，以表达导致其体外扩增的基因。在HSCs扩增后，通过多余的缺失和选择程序去除未整合的遗传物质，以产生一种严格安全、有效和易于管理的治疗方法，用于暴露于危及生命的剂量的电离辐射或化学制剂。

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.