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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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GENE THERAPY
Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes
Alan L. Parker,
Simon N. Waddington,
Campbell G. 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
From the British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom; Imperial College London, Gene Therapy Research Group, United Kingdom; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle; and Haemostasis and Thrombosis, Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, United Kingdom.
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 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 CAR-deleted 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.
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