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Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes

Parker, Alan L. ORCID:, Waddington, Simon N., Nicol, Campbell G., Shayakhmetov, Dmitry M., Buckley, Suzanne M., Denby, Laura, Kemball-Cook, Geoffrey, Ni, Shaoheng, Lieber, Andre, McVey, John H., Nicklin, Stuart A. and Baker, Andrew H. 2006. Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes. Blood 108 (8) , pp. 2554-2561. 10.1182/blood-2006-04-008532

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Upon local delivery, adenovirus (Ad) serotype 5 viruses use the coxsackie and Ad receptor (CAR) for cell binding and �v integrins for internalization. When administered systemically, however, their role in liver tropism is limited because CARpermissive and mutated viruses show similar biodistribution, a finding recently attributed to blood coagulation factor (F) IX or complement protein C4BP binding to the adenovirus fiber and “bridging” to either low-density lipoprotein receptorrelated protein or heparan sulfate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the vitamin K–dependent factors FX, protein C, and FVII in addition to FIX but not by prothrombin (FII), FXI, and FXII. This phenomenon was not dependent on proteolytic activation or cell signaling activity and for FX was mediated by direct virus-factor binding. Human FX substantially enhanced hepatocyte transduction by CAR-permissive and mutated viruses in an ex vivo liver perfusion model. In vivo, global down-regulation of vitamin K– dependent zymogens by warfarin signifi- cantly diminished liver uptake of CARdeleted Ads; however, this phenomenon was fully rescued by acute infusion of human FX. Our results indicate a common and pivotal role for distinct vitamin K– dependent coagulation factors in mediating hepatocyte transduction by adenoviruses in vitro and in vivo.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 24 Oct 2022 10:08

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