IEPA, a novel radiation countermeasure, alleviates acute radiation syndrome in rodents. Int J Radiat Biol 2025;101(1):1-14
Date
11/13/2024Pubmed ID
39531584Pubmed Central ID
PMC11698650DOI
10.1080/09553002.2024.2425312Scopus ID
2-s2.0-85209667085 (requires institutional sign-in at Scopus site)Abstract
Repurposing therapeutic agents with existing clinical data is a common strategy for developing radiation countermeasures. IEPA (imidazolyl ethanamide pentandioic acid) is an orally bioavailable small molecule pseudopeptide with myeloprotective properties, a good clinical safety profile, and stable chemical characteristics facilitating stockpiling. Here, we evaluated IEPA's radiomitigative efficacy in the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) using total-body irradiation (TBI) models in C57BL/6J mice and WAG/RijCmcr rats, applying various posology schemes and introducing syringe feeding of the IEPA formulation in the pudding. Additionally, we assessed IEPA in the delayed effects of acute radiation exposure (DEARE) model after partial-body irradiation (PBI) in WAG/RijCmcr rats. Endpoints included survival, body weight, hematology, and pulmonary parameters, depending on the model. Results from mouse and rat TBI models demonstrated survival improvements with repeated IEPA dosing at 10 mg/kg, with the largest benefits observed in the bi-daily (BID) treatment over the 30-day ARS phase in female rats. Survival across PBI-DEARE subsyndromes was comparable between IEPA and vehicle groups, though IEPA improved pulmonary parameters in female rats during the lung-DEARE phase. Sex-related differences in response to irradiation and IEPA were noted, with females showing a survival advantage. IEPA treatment is compatible with Neulasta® (Pegfilgrastim; PEG-G-CSF); adequately powered studies are needed to confirm the trend toward improved survival over standard care alone. IEPA is a promising development candidate as a medical countermeasure against the effects of acute radiation syndrome. Further confirmatory studies in small and large animal models should validate the robustness and translatability of preliminary rodent data on IEPA's radiomitigative efficacy.
Author List
Wesolowski R, Fish BL, Eibl M, Bähr S, Munjal Mehta S, Czajkowski MT, Gasperetti T, Orschell CM, Asang C, Singh N, Himburg HA, Pleimes DAuthor
Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute Radiation SyndromeAnimals
Female
Imidazoles
Male
Mice
Mice, Inbred C57BL
Radiation-Protective Agents
Rats
Whole-Body Irradiation