A Novel Recombinant Protein for Mitigating Total Body Radiation Injury

描述（由申请人提供）：SBIR I期提案旨在证明开发一种新型有效的急性辐射损伤治疗剂的可行性。核恐怖主义的威胁仍然很高，核电站有可能发生泄漏，这两种情况都可能造成大规模的急性辐射损伤。目前，没有治疗剂可用于减轻或治疗大规模照射环境中的急性辐射损伤。因此，迫切需要一种有效的缓解剂来治疗暴露于急性辐射的人。乳脂肪球表皮生长因子-因子VIII（MFG-E8）被确定为一种潜在的有效的辐射缓解剂，基于其增强凋亡细胞清除、减少炎症和维持肠屏障稳态的能力。使用大鼠全身照射（TBI）模型，我们发现给予重组人MFG-E8（rhMFG-E8）7天可使暴露于10-戈伊TBI的大鼠的存活率从载体中的30%分别增加到TBI后24小时和48小时开始治疗时的75%和60%。rhMFG-E8减少体重减轻，改善肠完整性，增加绒毛长度，降低TBI后杯状细胞与肠上皮细胞的比例。此外，rhMFG-E8降低辐射损伤后的肠道通透性，导致细菌移位和内毒素血症的减少。此外，我们还生产了具有生物活性的rhMFG-E8，纯度>99%，可用于未来的商业化。基于这些新的发现，我们假设rhMFG-E8可以被开发为急性辐射损伤的有效暴露后缓解剂。在这个建议中，我们将确定最佳剂量 的rhMFG-E8以拯救暴露于TBI的小鼠和rhMFG-E8在TBI后24小时治疗小鼠的剂量修正因子（DMF）。我们还将评估rhMFG-E8对暴露于TBI的小鼠的造血和胃肠道损伤的影响。我们的最终目标是获得FDA批准，使用rhMFG-E8作为大规模暴露环境中急性辐射损伤患者的安全有效治疗。

DESCRIPTION (provided by applicant): This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic agent for acute radiation injury. The threat of nuclear terrorism remains high and there is a possibility of a nuclear power plant leak, both of which can cause acute radiation injury at a large scale. Currently, there are no therapeutic agents available for the mitigation or treatment of acute radiation injury in a setting of mass exposure. Thus, there is an urgent unmet medical need for an effective mitigator to treat people exposed to acute radiation. Milk fat globule epidermal growth factor-factor VIII (MFG-E8) was identified as a potential effective radiation mitigator based on its ability to enhance apoptotic cell clearance, reduce inflammation, and maintain intestinal barrier homeostasis. Using a rat model of total body irradiation (TBI), we have discovered that administration of recombinant human MFG-E8 (rhMFG-E8) for 7 days increased the survival rate of rats exposed to 10-Gy TBI from 30% in the vehicle to 75% and 60% when treatment was initiated at 24h and 48h post-TBI, respectively. rhMFG-E8 reduced body weight loss and improved the intestinal integrity with increased villus length and reduced Goblet cell to enterocyte ratio after TBI. Moreover, rhMFG-E8 decreased gut permeability after radiation injury, leading to a reduction of bacterial translocation and endotoxemia. In addition, we have produced biologically active rhMFG-E8 with >99% purity for future commercialization. Based on these novel findings, we hypothesize that rhMFG-E8 can be developed as an effective post-exposure mitigator for acute radiation injury. In this proposal, we will determine the optimal dose of rhMFG-E8 to rescue mice exposed to TBI and the dose modification factor (DMF) of rhMFG-E8 to treat mice 24h post-TBI. We will also evaluate the effect of rhMFG-E8 on hematopoietic and gastrointestinal damages in mice exposed to TBI. Our ultimate goal is to obtain the FDA approval to use rhMFG-E8 as a safe and effective treatment for victims suffering from acute radiation injury in a large scale exposure setting.