Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein

Background & Aims: Genetic diseases reflecting abnormal hepatocyte function are potentially curable through gene therapy. Retroviral vectors offer the potential for permanent correction of such conditions. These vectors gener ally require cell division to occur to allow provirus:entry into the nucleu s, initiated in many experimental protocols by partial hepatectomy. We have explored methods to improve the efficiency of retroviral gene transfer tha t avoid the need for liver damage, Methods: Triiodothyronine (T3) and kerat inocyte growth factor (KGF) were used to induce hepatic proliferation in ra ts. The effects of intraportal and peripheral administration of a modified retrovirus that encoded the Lac Z gene during growth factor-induced liver h yperplasia were analyzed. Results: T3 Initiated hepatocyte proliferation mi dzonally; after KGF, proliferation was more diffuse. Optimal concentrations of T3 and KGF acted synergistically to induce proliferation in 61% of hepa tocytes in the intact liver. This enabled in vivo hepatocyte transduction, leading to gene expression by up to 7.3% of hepatocytes after intraportal r etroviral vector administration and 7.1% after peripheral venous administra tion. Conclusions: T3 and KGF act synergistically to induce hepatocyte prol iferation in undamaged liver. The liver can be simply transduced with integ rating vectors via the peripheral venous system during a wave of growth fac tor-induced proliferation.