HBV-DERIVED PROMOTERS DIRECT LIVER-SPECIFIC EXPRESSION OF AN ADENOVIRALLY TRANSDUCED LDL RECEPTOR GENE

In vivo approaches to liver gene therapy will require restriction of t ransgene expression to hepatocytes. Since targeting of viral vectors e xclusively to the liver is not easy to achieve, use of liver-specific promoters for driving expression of therapeutic genes is an interestin g alternative. We have shown previously that regulatory elements of th e hepatotropic hepatitis B virus (HBV) are strong and liver-specific i n vitro and therefore might be useful in hepatic gene therapy. Here we describe recombinant adenoviruses in which the human LDL receptor gen e is under the transcriptional control of the HBV core promoter, the c ore promoter linked directly to HBV enhancer I, or a HBV-CMV hybrid pr omoter, respectively. These viruses allowed for a moderate to strong e xpression of the LDL receptor gene in vitro in a hepatocyte-specific m anner when compared with the CMV immediate-early promoter. In vivo exp eriments demonstrated that the promoter gave rise to an expression lev el comparable to that from the CMV promoter in mouse liver, but was ve ry weak in lung and skeletal muscle. Thus, the HBV-CMV hybrid promoter is strong and hepatocyte specific both in vitro and in vivo even in t he adenoviral context and would be a good choice for driving a therape utic gene in liver gene therapy.