Advanced development of multi-omics based assays to predict late radiation organinjuries - the DEARE-Watch project

Groundbreaking research has led to the successful development of countermeasures against acute radiation toxicity, thereby significantly increasing the chance of survival of victims of a radiological accident. However, survivors of acute radiation syndrome (ARS) are at risk for developing delayed pathologies to vital organs such as the lung and kidney in the ensuing months to years after exposure. This is evidenced in victims of accidental radiation exposures, where radiation-induced lung injury has been reported in more than 50% of exposed victims. Additionally, in a cohort analysis of Japanese atomic bomb survivors, radiation dose was significantly associated with progressive chronic kidney disease. Therefore, the availability of FDA-approved predictive algorithms for risk assessment of late radiation injury remains an urgent and unmet need for managing a radiological emergency. Minimally invasive biomarkers that predict the development of radiation injuries in particular organ systems would enable targeted disease monitoring and early therapeutic interventions that minimize radiation induced degenerative effects on tissues and organs. Our previous work with rodent models of partial body X-ray or γ-ray exposures led to the development of liquid chromatography-mass spectrometry-based multi-omics panels that, when dysregulated in plasma and urine within the first month after irradiation predict late injury to the lung (LungWatch) and kidney (KidneyWatch) with high specificity and sensitivity. However, further studies are needed to enable wider implementation of these predictive biomarker panels. The goal of this application is to expand our biomarker panels for use in understudied populations and incorporate these, together with software for analysis and visualization of risk into prototype LungWatch and KidneyWatch devices, to present to the FDA. Using our well-characterized WAG/RijCmcr rat model of total and partial body irradiation, we will determine the impact of treatment with an FDA-approved ARS mitigator, radiation type (X-ray and γ-rays) and age (adult and juvenile) on the performance of the LungWatch panel in plasma and KidneyWatch panel in urine (Aim 1). Subsequently, we will validate the plasma and urine panels in irradiated non-human primates and establish baseline thresholds of the biomarkers in samples that represent the general human population, to enable unambiguous risk classification in humans (Aim 2). These rigorous biomarker studies along with the development of new algorithms for companion software required for automated analysis and interpretation of biomarker data, will allow us to develop target product profiles and documentation for FDA biomarker qualification for KidneyWatch and LungWatch device(s) (Aim 3). Taken together, we will develop kit-based multi- omics assays with automated classification algorithms that are amenable to high-throughput screening, to distinguish between individuals with and without elevated risk of radiation induced lung or kidney injury after a mass casualty event. Project Number: 1U01AI189442-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Amrita Cheema (+2 co-PIs) | Institution: GEORGETOWN UNIVERSITY, WASHINGTON, DC | Award Amount: $570,849 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZAI1 MMO-I (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U01AI18944201