Hepatic Gene Therapy: Persistent Expression of Human α1-Antitrypsin in Mice after Direct Gene Delivery In Vivo

The liver represents an excellent target organ for gene therapy. The current strategy for hepatic gene therapy involves the isolation of primary hepatocytes from a resected liver lobe, transduction of therapeutic genes in vitro followed by autologous hepatocellular transplantation. This ex vivo approach is a rather complex procedure in its entirety; thus, a simple method for direct gene delivery into hepatocytes in vivo has been developed. The procedure involves partial hepatectomy followed by the portal vein infusion of recombinant retroviral vectors. Histological analysis of hepatocytes after in vivo delivery of a recombinant retrovirus bearing the E. coli (β-galactosidase gene showed that 1–2% of the parenchymal cells were transduced. Direct hepatic transfer of human α1-antitrypsin cDNA under the transcriptional direction of the albumin promoter–enhancer led to constitutive expression of the human protein in the sera of recipients at concentrations of 30–1,400 ng/ml for at least 6 months. The experimental animals showed no signs of illness and histologic analysis of the liver revealed no evidence of pathologic abnormalities. The results suggest that the in vivo approach is an attractive alternative for hepatic gene therapy.

Overview summary

The liver represents a major target organ for gene therapy. A simple method for direct retroviral-mediated gene delivery into mouse hepatocytes in vivo was developed. By using a vector that encodes a human serum protein marker it was possible to demonstrate long-term constitutive expression in the sera of recipients. This approach represents an attractive alternative to the complex ex vivo strategy that is currently being used for hepatic gene therapy.