Assessment of efficiency and safety of adenovirus mediated gene transfer into normal and damaged murine livers

Background-When recombinant adenoviruses are infused directly into the circ ulation, transgene expression is almost completely restricted to the liver. Aims-Efficiency and safety of adenovirus mediated gene transfer into damage d livers were examined in mice with liver cirrhosis or fulminant hepatitis. Methods-Liver cirrhosis and fulminant hepatitis were induced by intraperito neal administration of thioacetamide and D-galactosamine followed by lipopo lysaccharide, respectively. Mice were infused with adenoviruses carrying th e Escherichia coli beta-galactosidase gene, lacZ gene, into the tail vein. Transduction efficiency of the lacZ gene was estimated histochemically by X -gal staining and quantitatively using a chemiluminescent assay. Activation of adenovirus specific T cells and development of neutralising antibodies against adenovirus were also examined. Results-Histochemical evaluation revealed that approximately 40%, 80%, and 40% of cells in normal, cirrhotic, and fulminant hepatitis livers, respecti vely, were stained blue using X-gal staining. Quantitative analyses reveale d that levels of lacZ expression in cirrhotic livers were approximately 2.5 -fold and sixfold greater than those in normal and fulminant hepatitis live rs, respectively. Although transgene expression in fulminant hepatitis live rs was significantly lower than that in normal livers, marked levels of tra nsgene expression were achieved even in fulminant hepatitis livers. Signifi cant adverse effects of adenoviruses were not observed in damaged livers. T here were no significant differences in cellular or humoral immune response s to adenoviruses among animals with normal, cirrhotic, and fulminant hepat itis livers. Conclusions-Our results suggest that gene therapy with adenoviruses may be used efficiently and safely, even in patients with severe liver disease.