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A Novel Recombinant Protein for Mitigating Acute Radiation Injury

一种用于减轻急性放射损伤的新型重组蛋白

基本信息

批准号：
10376745
负责人：
Wayne Chaung
金额：
$ 97.44万
依托单位：
THERASOURCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-10 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376745
关键词：
Accidents Acute Apoptosis Bacterial Translocation Biological Biological Assay Blood Body Weight Bone Marrow Cells Clinical Trials Coagulation Process Colony-Forming Units Assay Disasters Dose Drug Kinetics E-Selectin Endothelial Cells Epidermal Growth Factor Escherichia coli Evaluation Exposure to FDA approved Factor VIII Future Glycoproteins Goals Heart Hematopoietic Hepatic Histologic Homeostasis Human Human Milk Inflammation Injury Intestinal permeability Intestines Kidney Lethal Dose 50 Liver Lung Maximum Tolerated Dose Modification Monitor Mus Nuclear Nuclear Power Plants Oncogenic Pharmaceutical Preparations Pharmacology Phase Proteins Radiation Radiation Dose Unit Radiation Dose-Response Relationship Radiation Injuries Radiation Toxicity Radiation exposure Radioactive Rattus Recombinant Proteins Recombinants Regimen Safety Saline Small Business Innovation Research Grant Small Intestines Smooth Muscle Spleen Terrorism Testing Therapeutic Thick Time Toxicokinetics War Whole-Body Irradiation acute toxicity angiogenesis animal efficacy base carcinogenicity cell bank cytokine effective therapy efficacy study gamma irradiation gastrointestinal healing immunogenicity improved intestinal barrier irradiation medical countermeasure mesenteric lymph node milk fat globule nonhuman primate novel novel therapeutics phase 1 study programs protective effect public health relevance subcutaneous treatment duration von Willebrand Factor x-ray irradiation

项目摘要

PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop recombinant human MFG-E8 (rhMFG-E8) as a radiation medical countermeasure (MCM) towards its approval by the FDA in the future. Nuclear terrorism and major nuclear power plant leaks can cause acute radiation injury on a large scale. Currently, there are limited drugs available to treat acute radiation syndrome (ARS). rhMFG-E8 is a secretory glycoprotein that can maintain intestinal barrier homeostasis, enhance the clearance of dying cells, and reduce inflammation. In our Phase I studies, we have shown that endogenous MFG-E8 is downregulated after radiation injury, and treatment with E. coli-expressed His-tagged rhMFG-E8 improved the survival, body weight, and intestinal integrity of rats exposed to gamma irradiation. However, E. coli-expressed His-tagged proteins are inappropriate for the use in humans. Therefore, we have generated tag-free rhMFG-E8 using human cells, significantly enhancing rhMFG-E8’s biological activities. We have shown that tag-free rhMFG-E8 significantly improved the survival, body weight, and intestinal integrity of mice exposed to X-ray irradiation. We also determined rhMFG-E8’s pharmacokinetics, possible lack of mutagenicity, and short-term (3 months) stability. Based on the above positive results, we hypothesize that human cell-expressed tag-free rhMFG-E8 can be developed as an effective and safe post-exposure mitigator of acute radiation injury. In this proposal, we will assess tag-free rhMFG-E8’s efficacy as a radiation MCM in mice with the gastrointestinal acute radiation syndrome (GI-ARS) and hematopoietic acute radiation syndrome (H-ARS). In addition, we will determine the therapeutic window and effects of reduced treatment duration after radiation exposure, as well as rhMFG-E8’s safety and potential oncogenicity and immunogenicity. These proposed studies should provide crucial information on the efficacy and safety of rhMFG-E8 as a novel radiation MCM targeting GI-ARS and combined GI- and H-ARS. Our ultimate goal is to obtain FDA approval to use rhMFG-E8 as a safe and effective treatment for victims suffering from severe ARS.

项目描述：这项SBIR第二期提案旨在进一步开发重组人 MFG-E8(rhMFG-E8)作为美国FDA批准的放射医学对策(MCM) 未来。核恐怖主义和重大核电站泄漏可在很大程度上造成急性辐射损伤比例。目前，可用于治疗急性辐射综合征(ARS)的药物有限。RhMFG-E8是一种分泌型糖蛋白，可以维持肠道屏障的动态平衡，增强死亡细胞的清除，并减少炎症。在我们的第一阶段研究中，我们已经表明内源性MFG-E8被下调辐射损伤后，用大肠杆菌表达的hMFG-E8标记的重组人MFG-E8治疗提高了存活率，体内大鼠的体重和肠道完整性。然而，表达His的大肠杆菌标记了蛋白质不适合在人类身上使用。因此，我们使用以下命令生成了无标签的rhMFG-E8 人细胞，显著增强重组人MFG-E8‘S的生物学活性。我们已经证明了无标签的rhMFG-E8 显著改善X射线照射小鼠的存活率、体重和肠道完整性。我们还测定了重组人MFG-E8‘S的药代动力学、可能的无致突变性和短期(3个月)。稳定性。基于上述阳性结果，我们推测人细胞表达无标签的重组人MFG-E8 可被开发为一种有效和安全的急性辐射损伤后暴露后缓释剂。在这份提案中，我们将评估无标签的重组人MFG-E8‘S作为一种放射性MCM对胃肠道急性白血病小鼠的疗效。放射综合征(GI-ARS)和血液性急性辐射综合征(H-ARS)。此外，我们还将确定辐射照射后缩短治疗持续时间的治疗窗口和效果作为重组人MFG-E8‘S的安全性、潜在致瘤性和免疫原性。这些拟议的研究应该提供重组人MFG-E8作为靶向GI-ARS的新型放射MCM的有效性和安全性的关键信息联合使用GI-和H-ARS。我们的最终目标是获得FDA的批准，使用rhMFG-E8作为安全和对患有严重急性呼吸综合征的患者进行有效治疗。