miRNA Biomarkers for Diagnosis and Prediction of Radiation Induced Injury
T2014-204 A minimally invasive procedure to determine radiation toxicity in victims of nuclear events or radiation therapy patients.
The lack of a reliable radiation biodosimeter has been a major barrier to medical decision-making regarding the triage and treatment of persons - civilians, soldiers and first-time responders - who might be at risk for developing acute radiation syndromes (ARS) following nuclear events (e.g. nuclear weapon detonation, reactor accidents, "dirty bomb" assaults). ARS is an acute illness caused by exposure of the entire body to high-dose, penetrating radiation. Such exposure affects the hematopoietic, gastrointestinal, and central nervous systems and the different syndromes clinically manifest depending on exposure level. Rapid diagnosis is critical for emergency management, as demonstrated by the dramatic increase in survival rates if countermeasures and mitigators are administered within the first two days.
Currently, three criteria are used to determine radiation exposure level: clinical observation, lymphocyte depletion kinetics, and the dicentric chromosome assay. However, patient-to-patient variability greatly decreases the accuracy of clinical diagnosis. In addition, lymphocyte depletion kinetics requires three days of analysis for a crude dosimetry reading and 11 days for an accurate reading, and the dicentric chromosome assay is highly technical and labor intensive. By the time the level of radiation dosing/injury can be identified, significant and irreversible damage has already occurred in exposed individuals. New methods for early quantitation of absorbed radiation dose and prediction or detection of injury need to be developed.
Researchers at the Ohio State University, led by Dr. Naduparambil Jacob, have identified multiple biomarkers for use in radiation biodosimetry. Biomarkers miR-150 and miR-23a (normalizer), drawn in 1-2 drops of blood from a finger stick procedure, effectively detect early ARS in either the hematopoietic or gastrointestinal system. These biomarkers are responsive 24-48 hours after exposure and are stable for several days. They are effective for triaging those with minimal exposure (the "worried well") from those with substantial but treatable exposure. The latter group can be triaged with an exposure resolution of 0.5 Gy, allowing for greater precision in the choice of treatment regime. Made available in field deployable dosimeter devices, this early, accurate detection of dose and dose response will allow timely administration of countermeasures to mitigate acute toxicities and reduce late effects.
The Jacob research group has also identified a panel of miRs useful in the field of clinical radiation oncology as a means of evaluating toxicities in patients undergoing thoracic radiotherapy. A significant application is in the diagnosis of radiation-induced lung injury, a major issue for cancer patients (e.g. breast, lung, lymphoma) receiving lung-directed radiation therapy. Clinical manifestation of radiation injury is delayed, appearing 1-6 months following treatment (pneumonitis) and 6-24 months following treatment (lung fibrosis). At these time points, it is often too late for therapeutic intervention to preserve lung function. This OSU biomarker panel can detect such lung injury within two weeks of exposure, allowing for effective, early treatment long before clinical disease expression. Both the radonc and ARS dosimetry applications have been established in multiple model organisms and in specimens from human cancer patients who received therapeutic radiation.
- Triage and treatment selection for individuals exposed to a nuclear event
- Early evaluation of radiation toxicity allowing effective treatment measures in patients undergoing radiation therapy
- High sensitivity biodosimetry for ARS triage
- Dose response validated in multiple animal models and human TBI patient samples
- Distinguish >= 2 Gy whole body exposed vs unexposed - within 24 hours after exposure
- Feasibility tested in humans with small sample volume - 1-2 drops of blood finger stick
- Functional significance of key biomarkers validated in genetic model
- Short processing/assay time: collection to results in less than six hours
- Favorable kinetics, broad analytical range allows early detection at higher dose range