Portal Branch Occlusion Safely FacilitatesIn VivoRetroviral Vector Transduction of Rat Liver

Abstract

Hepatic gene therapy might correct the clinical manifestations of several genetic disorders in patients. Although retroviral vectors with a strong liver-specific promoter can result in stable and therapeutic levels of expression of genes from the liver, application of these techniques in humans is limited by the need to perform one or more invasive procedures to achieve ex vivo or in vivo transduction of hepatocytes. In vivo delivery involves injection of retrovirus into the portal vein during liver regeneration. Although transduction is efficient and specific for the liver, induction of hepatocyte replication requires a 70% partial hepatectomy or administration of a liver toxin. An alternative method for inducing hepatocyte replication is to occlude branches of the portal vein. This results in apoptosis of hepatocytes in the occluded lobes and compensatory replication of the hepatocytes in the nonoccluded lobes. We demonstrate here that portal branch occlusion is nearly as effective as partial hepatectomy at facilitating retroviral vector transduction in vivo and has a lower morbidity. Portal branch occlusion could be performed in larger animals by minimally invasive techniques and has been used safely to treat human patients with liver cancer. Portal branch occlusion might ultimately be used in humans to facilitate retroviral vector transduction in vivo for the treatment of genetic diseases. Retroviral vectors can result in long-term expression of genes from the livers of animals. However, the methods that have been used to transduce liver cells in vivo carry a significant risk to human patients. The goal of this study was to identify a safe method for facilitating retroviral vector transduction of liver cells in animals. Portal branch occlusion (PBO) was performed to induce liver cell replication, and a retroviral vector was injected into the portal vein at various times thereafter. Transduction was assessed by the level of expression of the serum protein human α₁-anti-trypsin in blood for 2 months after transduction. PBO was almost as effective as partial hepatectomy at facilitating retroviral vector transduction and had less morbidity. PBO might be used to facilitate in vivo retroviral transduction in humans for the purpose of gene therapy.