The role of vitamin K-dependent coagulation zymogens in adenovirus dissemination and pharmacodynamics in vivo. (360G-Wellcome-082939_B_07_Z)

This project will consider why delivery of adenoviral vectors via an intravascular route results in the majority of the virus being sequestered by the liver. Our aim is to improve delivery of adenoviral gene therapy vectors to extra-hepatic sites. We have shown a role for circulating blood coagulation factors with a homologous domain structure in mediating adenovirus transduction of hepatocytes in vitro. We have also shown a role for one of these factors (FX) in mediating transduction of liver in vivo using a virus defective in binding to the coxsackie adenovirus receptor. In this innovative project our aim is to investigate the contribution of individual clotting factors to this process. This project through a combination of cutting edge structure-function, in vitro and in vivo studies will provide the basis for the development of pharmaceutical approaches to modulate virus delivery in vivo. Our specific objectives are: · To study the interaction of individual clotting factors with the adenovirus capsid to define the structure function relationship · To study in detail the role of coagulation proteins in adenovirus transduction of hepatocytes in vitro · To study in detail the role of coagulation proteins in adenovirus transduction of liver in vivo.