权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock

rhMFG-E8 作为失血性休克的有效辅助疗法

基本信息

批准号：
9204427
负责人：
Weng-Lang Yang
金额：
$ 11.25万
依托单位：
THERASOURCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-08 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204427
关键词：
ADME Study Adjuvant Adjuvant Therapy Adult Age-Years American Animal Model Animals Apoptosis Apoptotic Binding Biological Biological Assay Blood Blood flow Brain Cardiac Output Cause of Death Cells Cessation of life Chromatography Circular Dichroism Clinical Trials Creatinine Discipline of obstetrics Dose Drug Kinetics Electroconvulsive Therapy Endotoxins Epidermal Growth Factor Escherichia coli Excretory function Future Goals Half-Life Heart Hemorrhage Hemorrhagic Shock Hepatic High Pressure Liquid Chromatography Histologic Hospitals Hour Human Human Milk Individual Inflammatory Injectable Injection of therapeutic agent Injury Interleukin-1 Interleukin-1 beta Interleukin-6 Intravenous Kidney Label Lactated Ringer&apos s Solution Large Intestine Lethal Dose 50 Liquid substance Liver Lung Lysine Mass Spectrum Analysis Maximum Tolerated Dose Medical Monitor Muscle Neutrophil Infiltration Organ Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Production Proteins Rattus Recombinants Resuscitation Safety Saline Serum Skin Small Business Innovation Research Grant Small Intestines Spleen Stomach Stroke Volume Surgical complication Survival Rate TNF gene TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Time Tissues Toxic effect Trauma Traumatic injury United States Urine Western Blotting attenuation base cytokine drug development efficacy study gastrointestinal hemodynamics improved milk fat globule mortality novel novel therapeutics preclinical study pressure public health relevance standard of care success urinary vasoactive agent vector

项目摘要

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.

描述(申请人提供)：本项目的主要目标是进一步证明开发重组人乳脂球表皮生长因子8(rhMFG-E8)作为失血性休克患者复苏的一种新的有效辅助疗法的可行性。失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岁以下人群的主要死亡原因，失血性休克占创伤相关死亡的三分之一。即使在标准的护理和医院环境下进行治疗，10%的失血性休克患者也会在数小时内死亡。因此，迫切需要一种新的、有效的辅助治疗方法，以提高现有的容量和血管活性药物用于出血复苏的成功率。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治疗出血动物，观察到循环中的促炎细胞因子、中性粒细胞对肺的渗透和细胞凋亡显著减少。用rhMFG-E8治疗的存活率也几乎翻了一番，从43%增加到83%。因此，我们推测，rhMFG-E8可以进一步发展成为一种新的、有效的失血性休克辅助治疗方法。为了推进药物的开发，我们将生产一种新的非组氨酸标记的重组人MFG-E8，并对其生物学活性、均一性和折叠状态进行分析。然后，我们将确定rhMFG-E8在减少失血性休克引起的器官损伤、血流动力学不稳定、促炎细胞因子和组织学损害方面的剂量依赖效应。其提高失血性休克后存活率的治疗窗口将被调查。最后，我们将确定其在健康和出血动物身上的安全药理和药代动力学。我们未来的步骤(SBIR第二阶段及以后)将包括完成临床前研究，如ADME研究和对非啮齿动物物种的疗效研究，以及与护理标准进行比较。然后，我们将向FDA提交调查性新药(IND)申请，以启动临床试验。我们的最终目标是将rhMFG-E8作为一种安全有效的辅助药物用于失血性休克患者的复苏。