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Publication Detail
Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes in vitro and in vivo
  • Publication Type:
    Journal article
  • Publication Sub Type:
    JOUR
  • Authors:
    Parker AL, Waddington SN, Nicol CG, Shayakhmetov DM, Buckley SMK, Denby L, Kemball-Cook G, Ni S, Lieber A, McVey JH, Nicklin SA, Baker AH
  • Publication date:
    2006
  • Pagination:
    2554, 2561
  • Volume:
    108
  • Issue:
    8
  • Notes:
    Upon local delivery adenovirus serotype 5 viruses use the coxsackie and adenovirus receptor (CAR) for cell binding and av 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-related protein or heparan sulphate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the homologous vitamin K-dependent factors FX, protein C and FVII in addition to FIX, but not by related but structurally more divergent factors (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.
Abstract
Upon local delivery adenovirus serotype 5 viruses use the coxsackie and adenovirus receptor (CAR) for cell binding and av 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-related protein or heparan sulphate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the homologous vitamin K-dependent factors FX, protein C and FVII in addition to FIX, but not by related but structurally more divergent factors (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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