Prenylation InhibitionIn Vivo Efficacy

Most recently, the antiviral efficacy of FTIs was evaluated further in vivo using a new mouse model of HDV (Bordier et al. 2003). The latter was established by hydrodynamically transfecting HBV-transgenic mice with HDV-encoding plasmids, and was an extension of previous experiments performed with HDV alone (Chang et al. 2001). Immunohistochemistry reveals that up to 20%-30% of the hepatocytes in the thus treated HBV-transgenic mice express delta antigen, and replicated genomic RNA is readily detectable in the liver, as are HDV virions in the serum (Bordier et al. 2003). This was the first demonstration of HDV viremia in an immunocompetent mouse model, and the percentage of mouse hepatocytes expressing delta antigen is 10-50-fold greater than reported for mouse models using other techniques.

Cohorts of mice in which HDV viremia had been established in this manner were treated with single daily doses of the prenylation inhibitors FTI-277 or FTI-2153, or vehicle controls. Both drugs were very effective at clearing HDV from the serum (Bordier et al. 2003).

Because a pool of prenylated L-HDAg can accumulate before the initiation of treatment with FTIs, it might be predicted that the efficiency of clearing HDV from the serum would be proportional to the length of treatment with prenylation inhibitor. This indeed appears to be the case. About an 85% reduction in serum HDV titer was observed after 2 days of therapy. By 4 days of treatment, the serum levels of HDV were reduced ~95%, and they became undetectable by 7 days of therapy (Bordier et al. 2003).

In addition, similar levels of alanine transaminase - a marker of liver toxicity - were observed among all treatment groups. This argues against the possibility that a nonspecific hepatotoxic effect of the FTIs was responsible for their potent clearing of HDV viremia. Together these results represent a dramatic and clear first in vivo confirmation of the potential of FTIs as a novel class of antiviral agents. Moreover, the clinical relevance and importance for human HDV infections of these results is obvious.

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