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)：这项SBIR第一阶段提案旨在证明开发一种新的、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，存在核电站泄漏的可能性，这两种情况都可能造成大规模的急性辐射伤害。目前，还没有可用于减轻或治疗大规模暴露环境中的急性辐射损伤的治疗剂。因此，迫切需要一种有效的缓释剂来治疗暴露在急性辐射中的人，这一需求尚未得到满足。乳脂球表皮生长因子(MFG-E8)具有促进细胞凋亡、减轻炎症和维持肠道屏障稳态的能力，被认为是一种潜在的有效辐射缓释剂。在大鼠全身照射模型上，我们发现重组人MFG-E8(rhMFG-E8)连续7d可使10GyTBI大鼠的存活率从30%分别提高到伤后24小时和48小时开始治疗时的75%和60%。重组人MFG-E8通过增加绒毛长度和降低杯状细胞/肠细胞比例，减少了体重损失，改善了肠道完整性。此外，重组人MFG-E8还可降低辐射损伤后的肠道通透性，从而减少细菌移位和内毒素血症。此外，我们还生产了具有生物活性的重组人MFG-E8，纯度为99%，可用于未来的商业化。基于这些新的发现，我们假设重组人MFG-E8可以被开发为一种有效的暴露后缓解急性辐射损伤的药物。在这项提案中，我们将确定最佳剂量 重组人MFG-E8用于救治脑损伤小鼠，剂量修正因子(DMF)用于治疗脑创伤后24小时小鼠。我们还将评估重组人巨噬细胞集落刺激因子-E8对脑创伤小鼠造血和胃肠损伤的影响。我们的最终目标是获得FDA的批准，使用rhMFG-E8作为一种安全有效的治疗方法，用于在大规模照射环境中遭受急性辐射损伤的受害者。