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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes
Blood, Volume 108, No. 8, Year 2006
Notification
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Description
Upon local delivery, adenovirus (Ad) sero-type 5 viruses use the coxsackie and Ad receptor (CAR) for cell binding and αv integrins for internalization. When administered systemically, however, their role in liver tropism is limited because CAR-permissive 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 receptor-related 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 significantly 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. © 2006 by The American Society of Hematology.
Authors & Co-Authors
Parker, Alan L.
Unknown Affiliation
Waddington, Simon N.
Unknown Affiliation
Shayakhmetov, Dmitry M.
Unknown Affiliation
Buckley, Suzanne M.K.
Unknown Affiliation
Ni, Shaoheng
Unknown Affiliation
Lieber, André
Unknown Affiliation
McVey, John H.
Unknown Affiliation
Nicklin, Stuart A.
Unknown Affiliation
Baker, Andrew H.
United Kingdom, Glasgow
University of Glasgow
Statistics
Citations: 305
Authors: 9
Affiliations: 1
Identifiers
Doi:
10.1182/blood-2006-04-008532
ISSN:
00064971
Research Areas
Genetics And Genomics