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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2554-2561.
Prepublished online as a Blood First Edition Paper on June 20, 2006; DOI 10.1182/blood-2006-04-008532.
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Submitted April 14, 2006
Accepted June 7, 2006
Multiple Vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes in vitro and in vivo
Alan L Parker, Simon N Waddington, Campbell Nicol, Dmitry M Shayakhmetov, Suzanne M Buckley, Laura Denby, Geoffrey Kemball-Cook, Shaoheng Ni, Andre Lieber, John H McVey, Stuart A Nicklin, and Andrew H Baker*
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, UK
Imperial College London, Gene Therapy Research Group, Sir Alexander Fleming Building, London, UK
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
Imperial College London, Haemostasis and Thrombosis, MRC Clinical Sciences Centre, London, UK
* Corresponding author; email: ab11f{at}clinmed.gla.ac.uk.
Upon local delivery adenovirus serotype 5 viruses use the coxsackie and adenovirus receptor (CAR) for cell binding and   integrins for internalisation. When administered systemically, however, their role in liver tropism is limited since 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 sulphate 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 signalling 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 downregulation of vitamin K-dependent zymogens by warfarin significantly diminished liver uptake of CAR-deleted adenoviruses, 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.
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