Abstract
After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS) and higher-dose gastrointestinal acute radiation syndrome (GI-ARS) lethality. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in preclinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here, we report generation of an anti-ceramide 6B5 single-chain variable fragment (scFv) and show that s.c. 6B5 scFv delivery at 24 hours after a 90% lethal GI-ARS dose of 15 Gy mitigated mouse lethality, despite administration after DNA repair was complete. We defined an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis after radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ, and mouse survival. We posit that successful preclinical development will render anti-ceramide 6B5 scFv a candidate for inclusion in the Strategic National Stockpile for distribution after a radiation catastrophe.
Highlights
With the possibility of a radiation disaster by way of nuclear detonation, accident, or radiation dispersal device, urgency for safe and effective medical radiation countermeasures (MRMs) to mitigate radiation toxicities in the general population represents an unmet medical need [1]
We defined an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis after radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ, and mouse survival
We found that 6B5 scFv administration occurred after DNA damage repair (DDR) was complete, and, intestinal stem cell (ISC) preservation is independent of DDR
Summary
With the possibility of a radiation disaster by way of nuclear detonation, accident, or radiation dispersal device, urgency for safe and effective medical radiation countermeasures (MRMs) to mitigate radiation toxicities in the general population represents an unmet medical need [1]. The Project BioShield Act and Department of Health and Human Services estimate that a MRM must be effective when administered at 24 hours after a nuclear disaster, as this represents the anticipated minimum time necessary to mobilize treatment by first responders to a significant portion of the population of a major city This timing presents a conceptual challenge, as DNA repair, currently regarded as the exclusive event determining outcome of radiation damage to human tissue [2, 3], would likely be complete at 24 hours after the range of doses leading to the gastrointestinal acute radiation syndrome (GI-ARS; known as the radiation GI syndrome [RGS]) [4, 5]. The Withers and Elkind assay directly quantifies radiation dose-dependent lethality of the small intestinal crypt compartment, is predictive of eventual animal death from GI-ARS, and is considered a “gold standard” in the radiation field for evaluating normal tissue response to ionizing radiation
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