Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair Journal Article
| Authors: | Rotolo, J. A.; Fong, C. S.; Bodo, S.; Nagesh, P. K. B.; Fuller, J.; Sharma, T.; Piersigilli, A.; Zhang, Z.; Fuks, Z.; Singh, V. K.; Kolesnick, R. |
| Article Title: | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| 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. © 2021, Rotolo et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Journal Title: | JCI Insight |
| Volume: | 6 |
| Issue: | 8 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2021-04-22 |
| Start Page: | e145380 |
| Language: | English |
| DOI: | 10.1172/jci.insight.145380 |
| PUBMED: | 33724956 |
| PROVIDER: | scopus |
| PMCID: | PMC8119204 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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