This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic agent for acute radiation injury. The threat of nuclear terrorism remains high and there is a possibility of a nuclear power plant leak, both of which can cause acute radiation injury at a large scale. Currently, there are no therapeutic agents available for the mitigation or treatment of acute radiation injury in a setting of mass exposure. Thus, there is an urgent unmet medical need for an effective mitigator to treat people exposed to acute radiation. Milk fat globule epidermal growth factor-factor VIII (MFG-E8) was identified as a potential effective radiation mitigator based on its ability to enhance apoptotic cell clearance, reduce inflammation, and maintain intestinal barrier homeostasis. Using a rat model of total body irradiation (TBI), we have discovered that administration of recombinant human MFG-E8 (rhMFG-E8) for 7 days increased the survival rate of rats exposed to 10-Gy TBI from 30% in the vehicle to 75% and 60% when treatment was initiated at 24h and 48h post-TBI, respectively. rhMFG-E8 reduced body weight loss and improved the intestinal integrity with increased villus length and reduced Goblet cell to enterocyte ratio after TBI. Moreover, rhMFG-E8 decreased gut permeability after radiation injury, leading to a reduction of bacterial translocation and endotoxemia. In addition, we have produced biologically active rhMFG-E8 with >99% purity for future commercialization. Based on these novel findings, we hypothesize that rhMFG-E8 can be developed as an effective post-exposure mitigator for acute radiation injury. In this proposal, we will determine the optimal dose of rhMFG-E8 to rescue mice exposed to TBI and the dose modification factor (DMF) of rhMFG-E8 to treat mice 24h post-TBI. We will also evaluate the effect of rhMFG-E8 on hematopoietic and gastrointestinal damages in mice exposed to TBI. Our ultimate goal is to obtain the FDA approval to use rhMFG-E8 as a safe and effective treatment for victims suffering from acute radiation injury in a large scale exposure setting.
The threat of nuclear terrorism remains high and there is a possibility of nuclear power plant leaks, both of which can cause acute radiation injury in a large scale. Currently, there are no therapeutic agents available for the mitigation or treatment of acute radiation injury in a large scale setting. Thus, there is an urgent unmet medical need for an effective mitigator to treat people exposed to acute radiation. Our innovative and pioneering research led to the discovery that rhMFG-E8 has the potential to be developed as such a mitigator for radiation injury. The purpose of this project is to develop rhMFG-E8 as a novel and effective post-exposure (24h or later) mitigator for acute radiation injury in a large scale settin.