Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-04-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.145380 |
| _version_ | 1828914284333105152 |
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| author | Jimmy A. Rotolo Chii Shyang Fong Sahra Bodo Prashanth K.B. Nagesh John Fuller Thivashnee Sharma Alessandra Piersigilli Zhigang Zhang Zvi Fuks Vijay K. Singh Richard Kolesnick |
| author_facet | Jimmy A. Rotolo Chii Shyang Fong Sahra Bodo Prashanth K.B. Nagesh John Fuller Thivashnee Sharma Alessandra Piersigilli Zhigang Zhang Zvi Fuks Vijay K. Singh Richard Kolesnick |
| author_sort | Jimmy A. Rotolo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T19:51:45Z |
| format | Article |
| id | doaj.art-76b420606de142dd89228218364193f3 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-13T19:51:45Z |
| publishDate | 2021-04-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-76b420606de142dd89228218364193f32022-12-21T23:33:24ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-04-0168Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repairJimmy A. RotoloChii Shyang FongSahra BodoPrashanth K.B. NageshJohn FullerThivashnee SharmaAlessandra PiersigilliZhigang ZhangZvi FuksVijay K. SinghRichard KolesnickAfter 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.https://doi.org/10.1172/jci.insight.145380Stem cellsVascular biology |
| spellingShingle | Jimmy A. Rotolo Chii Shyang Fong Sahra Bodo Prashanth K.B. Nagesh John Fuller Thivashnee Sharma Alessandra Piersigilli Zhigang Zhang Zvi Fuks Vijay K. Singh Richard Kolesnick Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair JCI Insight Stem cells Vascular biology |
| title | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| title_full | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| title_fullStr | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| title_full_unstemmed | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| title_short | Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair |
| title_sort | anti ceramide single chain variable fragment mitigates radiation gi syndrome mortality independent of dna repair |
| topic | Stem cells Vascular biology |
| url | https://doi.org/10.1172/jci.insight.145380 |
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