Anti-Ceramide ScFv Prophylaxis for First Responders to a Limited Nuclear Attack.

IF 2.5 Q3 CELL BIOLOGY
Jin Cheng, Prashanth K B Nagesh, Regina Feldman, Tambudzai Shamu, Zhigang Zhang, Zvi Fuks, Richard Kolesnick
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引用次数: 0

Abstract

Background/aims: After 9/11, multiple government agencies instituted programs aimed at developing medical radiation countermeasures (MRCs) for two syndromes lethal within weeks of a limited nuclear attack; the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS). While re-purposing drugs that enhance marrow repopulation treats H-ARS, no mitigator protects GI tract.

Methods: We recently reported anti-ceramide 6B5 single-chain variable fragment (scFv) pre-treatment abrogates ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells, preventing GI-ARS lethality in C57B/L6J mice. Here, with US Department of Defense support, we provide evidence that humanized anti-ceramide scFv (CX-01) is a promising prophylactic MRC for first responders, who risk exposure upon entering a radiation-contaminated site.

Results: CX-01, when delivered up to 90 min before irradiation, is highly-effective in preventing small intestinal endothelial apoptosis in mice and lethality in both sexes. Unexpectedly, females require an ~2-fold higher CX-01 dose than males for full protection. CX-01 is effective subcutaneously and intramuscularly, a property critical for battlefield use. Increasing the maximally-effective dose 5-fold does not extend duration of bioeffectiveness.

Conclusion: While CX-01 prevents GI-ARS lethality, structural modification to extend half-life may be necessary to optimize first responder prophylaxis.

为有限核攻击的第一反应者提供抗神经酰胺 ScFv 预防疗法。
背景/目的:9-11事件后,多个政府机构制定了计划,旨在针对有限核攻击后数周内致命的两种综合征(造血-急性辐射综合征(H-ARS)和高剂量胃肠-急性辐射综合征(GI-ARS))开发医疗辐射对策(MRCs)。虽然促进骨髓再增殖的再利用药物可治疗 H-ARS,但没有缓解药物可保护胃肠道:方法:我们最近报道了抗神经酰胺6B5单链可变片段(scFv)预处理可抑制持续的小肠内皮细胞凋亡,从而挽救Lgr5+干细胞,防止C57B/L6J小鼠GI-ARS致死。在美国国防部的支持下,我们在此提供证据,证明人源化抗神经酰胺scFv(CX-01)对急救人员来说是一种很有前景的预防性MRC:结果:CX-01 在辐照前 90 分钟内给药,能高效防止小鼠小肠内皮细胞凋亡,并防止雌雄小鼠死亡。意想不到的是,雌性小鼠需要比雄性小鼠高出约 2 倍的 CX-01 剂量才能获得完全保护。CX-01 在皮下和肌肉注射中均有效,这一特性对战场使用至关重要。将最大有效剂量提高 5 倍并不会延长生物有效性的持续时间:结论:CX-01 可预防 GI-ARS 致死,但要优化第一反应者的预防措施,可能需要进行结构调整以延长半衰期。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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