Further Development of dmPGE2 as an Effective Radioprotectant and Radiomitigator for H-ARS and DEARE in Fulfillment of the Requirements for Product Development Under the Animal Rule
Abstract
Threats of radiologic warfare, terrorist use of radiological weapons, and nuclear accidents put our military Service members, military and non-military first responders, and the general population in proximity at risk for acute radiation exposure and stresses the need for medical preparedness to treat exposed individuals. Victims of high-dose radiation exposure will face a myriad of acute and chronic organ injuries requiring multifaceted treatment approaches. The hematopoietic system that forms all blood cells is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after significant exposure that, if untreated, leads to death within weeks from opportunistic infection and/or hemorrhage due to loss of white blood cells that fight bacteria and help blood clot. Survivors of ARS experience delayed effects of radiation exposure (DEARE), chronic illnesses that affect multiple organ systems, including bone marrow, immunity, heart and blood vessels, intestines, lung and kidneys, which become exacerbated with age. There are currently no drugs approved to protect personnel from radiation exposure. Several protein cytokines, Neupogen®, shown by our group to increase survival for H-ARS, Neulasta® (longer acting Neupogen), and Leukine®, have been licensed by the U.S. Food and Drug Administration (FDA) as medical countermeasures (MCM) to treat exposed individuals. While generally safe, rare life-threatening side effects have been reported. However, they have not shown efficacy for DEARE. There is therefore an unmet medical need for safe, effective MCM to protect and mitigate the acute and delayed effects of radiation exposure on hematopoiesis and multiple-organ systems. A radiological event cannot be predicted in advance. The civilian population will require MCM that prevent death or morbidity when administered after radiation exposure (radiomitigation), while military personnel and first responders require a MCM that prevents death or morbidity prior to exposure (radioprotection). Our studies performed in our Department of Defense (DoD) grant W81XWH-15-1-0254/55 using multifaceted organism, cellular, and genome approaches developed strategies for both radiomitigation and radioprotection and multiple organ DEARE in H-ARS survivors. In our model in mice that is predicative of the human response 16,16 dimethyl prostaglandin E2 (dmPGE2), an analog of PGE2, the major member of a lipid family involved in many physiologic systems, protects and stimulates survival pathways and self-renewal in the hematopoietic stem cells (HSC) responsible for blood cell production that are damaged by radiation exposure, and enhances survival and recovery of all hematopoietic lineages. In addition, dmPGE2 significantly reduces hematopoietic, immunological, cardiac, and renal DEARE, making it an ideal radioprotectant for further development for the benefit of the military, first responders, and civilians. While significant progress was made, challenges in identifying the specific receptor(s) that respond to dmPGE2 was encountered and while dmPGE2 was active in reducing DEARE when given before radiation, its activity when given after radiation was inconclusive, likely due to timing of administration. In this proposal, we will perform pharmacokinetics and biodistribution of dmPGE2 in normal and irradiated mice and in special populations and a repeat dose toxicology study to complete a pre-Investigational New Drug (IND) package to consult with FDA and fulfill much of the requirements of the FDA AR for MCM. We will use our current insight and new strategies to define the Prostaglandin E Receptor (EP) receptors involved in radioprotection and radiomitigation of H-ARS and DEARE, complete genome analysis of pathways affected by dmPGE2, and optimize the timing of administration of dmPGE2 for radiomitigation of DEARE. Our DoD W81XWH-15-1-0254/55 findings and the studies proposed herein will provid
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910573
Entities
People
- Christie Orschell
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army