A Novel Recombinant Protein for Mitigating Total Body Radiation Injury

一种用于减轻全身辐射损伤的新型重组蛋白

• 批准号: 8781840
• 负责人: Weng-Lang Yang
• 金额: $ 29.47万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781840
• 关键词: Acute; Animals; Apoptosis; Apoptotic; Bacterial Translocation; Biological Assay; Blood; Blood Circulation; Body Weight Changes; Body Weight decreased; Bone Marrow; C57BL/6 Mouse; Cells; Clinical Trials; Colony-forming units; Complete Blood Count; Detection; Dose; Drug Formulations; Drug Kinetics; Endotoxemia; Endotoxins; Enterocytes; Epidermal Growth Factor; Factor VIII; Future; Goals; Goblet Cells; Hematopoietic; Hematopoietic System; Homeostasis; Human; Inflammation; Inflammatory; Injection of therapeutic agent; Intestines; Length; Lethal Dose 50; Measurement; Medical; Mesentery; Modeling; Modification; Monitor; Mus; Nuclear; Nuclear Power Plants; Permeability; Phase; Property; Radiation; Radiation Dose-Response Relationship; Radiation Injuries; Rattus; Recombinant Proteins; Recombinants; Regulation; Research; Safety; Saline; Small Business Innovation Research Grant; Survival Rate; TdT-Mediated dUTP Nick End Labeling Assay; Terrorism; Therapeutic; Therapeutic Agents; Time; Villus; Whole-Body Irradiation; base; commercialization; comparative efficacy; cytokine; design; dosage; effective therapy; gastrointestinal; gastrointestinal system; granulocyte; improved; innovation; irradiation; lymph nodes; macrophage; milk fat globule; mortality; mouse model; novel; phase 2 study; preclinical study; public health relevance

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.

描述（由申请人提供）：该 SBIR 第一阶段提案旨在证明开发一种新型有效的急性放射损伤治疗剂的可行性。核恐怖主义威胁依然较高，存在核电站泄漏的可能性，两者都会造成大范围的急性辐射损伤。目前，没有可用于减轻或治疗大规模暴露环境下的急性放射损伤的治疗药物。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，但这一医疗需求尚未得到满足。乳脂球表皮生长因子 VIII (MFG-E8) 因其增强凋亡细胞清除、减少炎症和维持肠道屏障稳态的能力而被认为是一种潜在有效的辐射缓解剂。使用全身辐射 (TBI) 大鼠模型，我们发现，在 TBI 后 24 小时和 48 小时开始治疗时，给予重组人 MFG-E8 (rhMFG-E8) 7 天可将暴露于 10 Gy TBI 的大鼠的存活率从载体中的 30% 分别提高到 75% 和 60%。 rhMFG-E8 减少了体重减轻，改善了肠道完整性，增加了绒毛长度，降低了 TBI 后杯状细胞与肠上皮细胞的比例。此外，rhMFG-E8 降低了辐射损伤后的肠道通透性，从而减少了细菌易位和内毒素血症。此外，我们还生产了纯度 >99% 的生物活性 rhMFG-E8，以供未来商业化。基于这些新发现，我们假设 rhMFG-E8 可以开发为急性辐射损伤的有效暴露后缓解剂。在本提案中，我们将确定最佳剂量 rhMFG-E8 拯救暴露于 TBI 的小鼠，rhMFG-E8 的剂量修改因子 (DMF) 治疗 TBI 后 24 小时的小鼠。我们还将评估 rhMFG-E8 对暴露于 TBI 的小鼠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遭受急性辐射损伤的受害者的安全有效的治疗方法。