Validation of miRAD assay as a biodosimetry tool for radiological/nuclear triage applications in pediatric and geriatric population - PROJECT SUMMARY There has been a dire need for developing a rapid biodosimetry tool for triaging victims in the aftermath of any radiological/nuclear mass casualty incident(s). Rapid triage is critical for timely administration of medical countermeasures and proper allocation of resources, thus saving lives. Currently, there are no US Food and Drug Administration (FDA) approved tests or assays that allow early exposure categorization of victims for effective medical countermeasures. The current gold standard for radiation biodosimetry is the dicentric chromosome assay (DCA) but its application to mass casualty incidents is severely restricted as it requires 48- 72 hours for dose estimation. To provide a rapid absorbed dose estimation within a few hours, we have developed a highly sensitive test tracking two-microRNAs found in blood samples collected by a simple finger prick. The miRAD assay enables accurate does estimation in less than four hours, covering dose ranges and time points critical for medical intervention in victims. In the miRAD assay, radiation dose dependent changes in evolutionarily and functionally conserved miR150-5p in the blood is internally calibrated with miR23a-3p which is non-responsive to radiation as it is not expressed at a significant level in blood cells, yet abundant in blood and passively released into circulation from non-blood cells. Our assay, tested so far in blood samples from irradiated mice, non-human primates and human radiotherapy patients and has shown a great potential for development as an effective triage tool. Robustness of the baseline expression of both the responder and normalizer using blood samples collected by a finger prick has been validated in volunteers, including individuals afflicted with common chronic medical conditions. The kinetic response of the miRAD assay will favorably allow integration with other clinical signs (clinical symptoms, time of emesis) and help prioritize treatment in the “life savable” group. As further development and refinement of the assay for triage applications is needed, the current proposal is designed to test the accuracy of dose prediction by miRAD with the gold standard DCA by using an in vivo total body irradiated mouse model system. Since alteration in miR150-5p in blood after radiation exposure appears to be an intrinsic in vivo phenomenon, we will systematically compare the miRAD assay with DCA for absorbed dose validation in pediatric and geriatric population mimicking a heterogeneous human population. The assay has potential utility at different stages in radiological/nuclear disaster management, including early triage, precision dosimetry, follow-up and evaluation of countermeasures. Beyond its utility in radiation disaster preparedness and management, the assay will have utility in evaluation of bone marrow ablation and reconstitution kinetics in radiotherapy patients.
