The primary objective of this project is to demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective therapeutic for patients with acute kidney injury (AKI) associated with ischemia due to low renal perfusion. AKI is a major cause of prolonged hospitalization and increased mortality. Ischemic AKI often results from decreased renal blood flow associated with cardiac surgery involving cardiopulmonary bypass, especially coronary artery bypass graft and valve replacement. Despite being a frequent, life-shortening, and costly complication, no FDA-approved drugs are currently clinically available to treat ischemic AKI. MFG-E8 is a protein that promotes the clearance of inflammation-promoting dying cells and decreases the influx of tissue-damaging neutrophils to the injured site. In the preliminary study, we used recombinant mouse MFG-E8 to treat mice with AKI induced by severe renal ischemia-reperfusion. Treatment with recombinant mouse MFG-E8 significantly attenuated renal dysfunction, decreased levels of proinflammatory cytokines, and reduced kidney infiltration by neutrophils. Therefore, we hypothesize that rhMFG-E8 can be developed as a new and effective biologic drug to treat patients with ischemic AKI. Indeed, administration of His-tagged rhMFG-E8 increased the 10-day survival of mice with ischemic AKI from 47% to 68%. Since His-tagged proteins are not suited for use in humans, we have started to produce a druggable, human-like glycosylated, His tag-free rhMFG-E8 using a mammalian Chinese hamster ovary (CHO) cell expression system. In this project we will express, purify, and characterize CHO-expressed rhMFG-E8. We will next determine CHO-expressed rhMFG-E8's efficacy to attenuate renal injury and improve survival after ischemic AKI, and its pharmacokinetic (PK) profile in healthy and AKI animals. Our future steps (SBIR Phase II and beyond) include completing preclinical and safety studies, establishing ADME and safety studies, determining efficacy in a second species, and filing an investigational 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 biologic drug to treat patients with ischemic AKI.
During many common surgical procedures, such as coronary artery, heart valve replacement and cancer surgery, the blood flow to the kidneys may drop resulting in acute kidney injury. Acute kidney injury leads to a loss of kidney function, longer hospital stays, expensive treatments, and increased death. Yet, there is no good treatment for patients with acute kidney injury. We have shown that a protein called MFG-E8 strongly protects experimental animals from acute kidney injury and improves their survival. Therefore, we propose to develop the human form of MFG-E8 as a new and powerful way to treat surgery-associated acute kidney injury.
