Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair.
JCI Insight
; 6(8)2021 04 22.
Article
em En
| MEDLINE
| ID: mdl-33724956
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Mortalidade
/
Geral
/
Prevencao_e_fatores_de_risco
/
Agentes_cancerigenos
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Tratamento
Base de dados:
MEDLINE
Assunto principal:
Ceramidas
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Síndrome Aguda da Radiação
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Anticorpos de Cadeia Única
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Gastroenteropatias
/
Intestino Delgado
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
JCI Insight
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos