Hepatic gene therapy: persistent expression of human alpha 1-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 beta-galactosidase gene showed that 1-2% of the parenchymal cells were transduced. Direct hepatic transfer of human alpha 1-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.