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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.