IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG/RijCmcr rats when started 15 days after PBI with bone marrow sparing

Abstract

Purpose

To test IPW-5371 for the mitigation of the delayed effects of acute radiation exposure (DEARE). Survivors of acute radiation exposure are at risk for developing delayed multi-organ toxicities; however, there are no FDA-approved medical countermeasures (MCM) to mitigate DEARE.

Methods

WAG/RijCmcr female rat model of partial-body irradiation (PBI), by shielding part of one hind leg, was used to test IPW-5371 (7 and 20 mg kg⁻¹d⁻¹) for mitigation of lung and kidney DEARE when started 15 d after PBI. Rats were fed known amounts of IPW-5371 using a syringe, instead of delivery by daily oral gavage, sparing exacerbation of esophageal injury by radiation. The primary endpoint, all-cause morbidity was assessed over 215 d. Secondary endpoints: body weight, breathing rate and blood urea nitrogen were also assessed.

Results

IPW-5371 enhanced survival (primary endpoint) as well as attenuated secondary endpoints of lung and kidney injuries by radiation.

Conclusion

To provide a window for dosimetry and triage, as well as avoid oral delivery during the acute radiation syndrome (ARS), the drug regimen was started at 15 d after 13.5 Gy PBI. The experimental design to test mitigation of DEARE was customized for translation in humans, using an animal model of radiation that was designed to simulate a radiologic attack or accident. The results support advanced development of IPW-5371 to mitigate lethal lung and kidney injuries after irradiation of multiple organs.

Keywords:

• Mitigation
• DEARE
• partial body irradiation
• radiation pneumonitis
• radiation nephropathy

Acknowledgments

We would like to thank Dr. Yuri Sheinin Department of Pathology, Medical College of Wisconsin, for his expert help in scoring the lung histology.

Disclosure statement

B. Hart is the founder of Innovation Pathways and is currently developing IPW-5371 as a radiation Medical Countermeasure and other potential indications.

Notes

1 The pudding formulation used in the described PBI WAG rat experiment was not used in the referenced C57L/J mouse study. The WAG rats were fed the pudding formulation, the C57L/J mice were orally dosed by oral gavage, using an appropriate oral gavage formulation.

Additional information

Funding

This work was supported by funding from NIH/NIAID National Institute of Allergy and Infectious Diseases contract HHSN272201800012C Innovation Pathways, U01s AI133594 & AI107305, and Department of Radiation Oncology, MCW.

Notes on contributors

Brian L. Fish

Brian L. Fish is a normal tissue radiation biologist working with WAG/RijCmcr rats for the past 4 decades. He specializes in the delayed effects of radiation injury to normal tissues and the mitigation of DEARE.

Barry Hart

Barry Hart, founder, and CEO of Innovation Pathways is working to develop a medical countermeasure to treat the delayed effect of acute radiation exposure.

Tracy Gasperetti

Tracy Gasperetti is the Supervisor of the Radiation Biology lab at the Medical College of WI. She has more than 10 years’ experience in working with the WAG/RijCmcr rat strain.

Jayashree Narayanan

Jayashree Narayanan has worked with WAG/RijCmcr rats for the mitigation of radiation injury for the last 10 years. She also has expertise in analytical, biochemical, molecular, and histological techniques for over 3 decades.

Feng Gao

Feng Gao is a radiation biologist. She specializes in radiation-induced multi-organ injuries and mitigations.

Dana Veley

Dana Veley is a research technologist II. She assisted with daily drug administration, health monitoring, providing treatment, as well as the blood collection for this study.

Lauren Pierce

Lauren Pierce is a research technologist I. She assisted with monitoring the health of the rats, providing treatment, as well as collection of breathing rate data.

Heather A. Himburg

Heather A. Himburg, Ph.D., is an Associate Professor of Radiation Oncology and Biomedical Engineering at the Medical College of Wisconsin, WI.

Thomas MacVittie

Tom MacVittie, Radiation biologist experienced in small and large animal models for MCM development against the ARS and DEARE under the criteria of the FDA Animal Rule.

Meetha Medhora

Meetha Medhora is a Professor Emeritus of Radiation Oncology. She is a molecular biologist by training and has worked on radiation injury to the lung since 2005 and delayed effects of radiation to the kidneys and heart since 2012. Her goal is to create rat models of radiation injury and identify mitigators for the late effects of radiation exposure.