rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock

 描述（申请人提供）：本项目的主要目的是进一步证明开发重组人乳脂球表皮生长因子-8（rhMFG-E8）作为一种新型有效的失血性休克患者复苏辅助治疗的可行性。出血性休克是世界范围内死亡的主要原因。在美国，创伤性损伤是44岁以下人群死亡的主要原因，出血性休克占创伤相关死亡的三分之一。即使在医院接受标准治疗，10%的失血性休克患者在数小时内死亡。因此，对于能够提高现有容量和血管活性剂用于出血复苏的成功率的新型有效辅助疗法存在未满足的迫切需求。MFG-E8是一种促进凋亡/死亡细胞清除并抑制促炎细胞因子产生的蛋白质。在初步研究中，我们用rhMFG-E8治疗老年动物，并观察到循环促炎细胞因子、中性粒细胞浸润到肺和细胞凋亡的显著减少。用rhMFG-E8治疗也使存活率从43%增加到83%，几乎翻了一番。因此，我们推测rhMFG-E8可以进一步发展为一种新的和有效的辅助治疗失血性休克。为了推进药物开发，我们将生产一种新的非His标记的rhMFG-E8，并分析其生物活性，均一性和折叠状态。然后，我们将确定rhMFG-E8对减少由失血性休克引起的器官损伤、血流动力学不稳定性、促炎细胞因子和组织学损伤的剂量依赖性作用。将研究其改善失血性休克后存活率的治疗窗。最后，我们将确定其在健康和老龄动物中的安全药理学和药代动力学特征。我们未来的步骤（SBIR II期及以后）将包括完成临床前研究，如ADME研究和非啮齿类动物的疗效研究，以及与标准治疗进行比较。然后，我们将向FDA提交研究性新药（IND）申请，以启动临床试验。我们的最终目标是使rhMFG-E8作为一种安全有效的失血性休克患者复苏辅助药物获得商业利用。

 DESCRIPTION (provided by applicant): The primary objective of this project is to further demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective adjuvant therapy for the resuscitation of patients with hemorrhagic shock. Hemorrhagic shock is a major cause of mortality worldwide. In the United States, traumatic injury is the main cause of death in individuals younger than 44 years of age, and hemorrhagic shock accounts for one third of trauma-related deaths. Even when treated with the standard of care and in a hospital setting, 10% of patients with hemorrhagic shock die within hours. Therefore, there is an unmet and critical need for a novel and effective adjuvant therapy capable of improving the success rate of the existing volume and vasoactive agents for hemorrhage resuscitation. MFG-E8 is a protein that promotes the clearance of apoptotic/dying cells and inhibits the production of pro-inflammatory cytokines. In preliminary studies, we treated hemorrhaged animals with rhMFG-E8 and observed significant decreases in circulating pro-inflammatory cytokines, neutrophil infiltration to the lungs, and apoptosis. Treatment with rhMFG-E8 also nearly doubled the survival rate from 43% to 83%. Therefore, we hypothesize that rhMFG-E8 can be further developed as a new and effective adjuvant therapy for hemorrhagic shock. To advance the drug development, we will produce a new non His-tagged rhMFG-E8 and analyze its biological activity, homogeneity, and folding status. We will then determine the dose-dependent effects of rhMFG-E8 on reducing organ injury, hemodynamic instability, pro-inflammatory cytokines, and histological damage caused by hemorrhagic shock. Its therapeutic window to improve survival after hemorrhagic shock will be investigated. Finally, we will determine its safety pharmacology and pharmacokinetic profile in healthy and hemorrhaged animals. Our future steps (SBIR Phase II and beyond) will include completing preclinical studies, such as ADME studies and efficacy studies in a non-rodent species, as well as comparing with the standard of care. We will then file an investigative new drug (IND) application with the FDA to initiate clinical trials. Our ultimate goal is to obtain commercial utilization of rhMFG-E8 as a safe and effective adjuvant drug for the resuscitation of patients with hemorrhagic shock.