Liver-specific alpha 2 interferon gene expression results in protection from induced hepatitis

The current therapy for hepatitis B and C is based on systemic administrati on of recombinant human alpha interferon (r-hIFN-alpha). However, systemic delivery of r-hIFN-alpha is associated with severe side effects, but more i mportantly, it is effective in only a small percentage of patients. In an e ffort to maximize IFN-alpha antiviral efficacy, we have explored the therap eutic potential of murine IFN-alpha 2 (mIFN-alpha 2) selectively expressed in the liver. To this end, we have developed a helper-dependent adenovirus vector (HD) containing the mIFN-alpha 2 gene under the control of the liver -specific transthyretin promoter (HD-IFN), Comparison with a first-generati on adenovirus carrying the same mIFN-alpha 2 expression cassette indicates that at certain HD-IFN doses, induction of antiviral genes tan be achieved in the absence of detectable circulating mIFN-alpha 2. Challenge of injecte d mice with mouse hepatitis virus type 3 showed that HD-IFN provides high l iver protection. Moreover, liver protection was also observed in acute nonv iral liver inflammation hepatitis induced by concanavalin A at 1 month post infection. These results hold promise for the development of a gene therapy treatment for chronic viral hepatitis based on liver-restricted expression of IFN-alpha 2.