GENE-TRANSFER IN BABOONS USING PROSTHETIC VASCULAR GRAFTS SEEDED WITHRETROVIRALLY TRANSDUCED SMOOTH-MUSCLE CELLS - A MODEL FOR LOCAL AND SYSTEMIC GENE-THERAPY

Prosthetic vascular grafts containing retrovirally transduced autologo us vascular smooth muscle cells were studied as a model for introducti on of human genes into baboons. Retroviral vectors encoding beta-galac tosidase (beta-Gal) (LNPoZ) or human purine nucleoside phosphorylase ( LPNSN-2), a control gene, were used for ex vivo transduction of autolo gous baboon smooth muscle cells obtained from vein biopsies. Transduce d cells were placed into a collagen solution and seeded into the inter stices of polytetrafluoroethylene vascular grafts. Endothelial cells w ere then seeded onto the luminal surface of the grafts to reduce throm bus formation. One LNPoZ-seeded graft- and one LPNSN-2-seeded control graft were implanted bilaterally into the aorto-iliac circulation of e ach of 4 animals. All grafts remained patent until they were removed a fter 3-5 weeks and examined histochemically for vector-expressing cell s. All histological cross-sections from the beta-Gal vector seeded gra fts contained cells staining blue with the X-Gal chromogen. For the fo ur grafts, the mean fraction of LNPoZ expressing cells was 10%, with a range of 2-20%, while no sections from the control grafts contained s tainable cells. Smooth muscle cells expressing the reporter gene were localized within the graft wall but not in the newly forming intima or outer capsule of fibrous tissue. Implantation of transduced cells wit hin this type of vascular graft may provide a useful approach for long -term local and systemic gene therapy.