A stent-graft is a conduit composed of a polymer membrane supported by a metal stent that is placed in a vessel using catheter technology. We have genetically engineered vascular smooth muscle cells (SMC) and placed them on a stent graft that was specifically designed to shelter the SMC cells from implantation trauma. We found that these genetically engineered cells survived and proliferated and that gene expression was maintained at high levels over a long period, indicating the feasibility of this new gene therapy strategy to deliver the gene product directly into the bloodstream. The objective of this project is to explore whether a stent-graft suffused with genetically engineered SMC can be used to deliver functional Factor IX (F.IX) to treat hemophilia B. Hemophilia B is an X-linked bleeding diathesis resulting from a deficiency of blood coagulation factor IX. Hemophilia is an ideal model for gene therapy because precise regulation and tissue-specific transgene expression are not required. We will use a hemophilic dog model to study the feasibility of bioengineering a stent graft for gene therapy. We hypothesize that the intravascular delivery of F. IX using a stent-graft suffused with retrovirally transduced SMC will offer the opportunity for delivery of F.IX at a therapeutic level to correct the coagulation defect. We will first determine how long and how much of the transgene product canine F.IX can be produced from the bioengineered stent grafts after being implanted into the aorta of a hemophilia B dog using catheter technology. We will modulate the level of F.IX production by the length of the implanted stent graft. Then, we will determine whether the secreted F. X at these levels can ameliorate the coagulation defect in a hemophilic dog by measuring coagulation parameters. The host immune response to the transgene product canine F.IX will also be examined. The outcome of the project will have direct applications in the treatment of hemophilia as well as other blood and vascular disorders.