ADENOVIRUS-MEDIATED BETA-GALACTOSIDASE GENE DELIVERY TO THE LIVER LEADS TO PROTEIN DEPOSITION IN KIDNEY GLOMERULI

The many cell types of the kidney, precisely arranged, allow this orga n to perform its complex physiologic functions. However, this architec tural complexity makes gene transfer into the kidney difficult. One ap proach to delivering a therapeutic protein to the kidney is to transfe r a gene to a non-renal tissue. Release of the protein into the circul ation might then result in deposition in the kidney, if the protein ha s the appropriate molecular properties. In this study, we found that p arenterally administered replication deficient adenovirus carrying the beta-galactosidase gene resulted in intense beta-galactosidase gene e xpression in hepatocytes. As a result of immune attack on transduced h epatocytes, beta-galactosidase protein from these cells is released in to the circulation, transported, and deposited almost exclusively in k idney glomeruli. Intense beta-galactosidase activity was noted in both kidneys with a peak at two weeks following viral administration, conc urrent with loss of beta-galactosidase positive hepatocytes. Consisten t with our hypothesis of protein transfer, no beta-galactosidase mRNA was detected in glomeruli. Moreover, systemically administered protein generated similar glomerular beta-galactosidase activity. Finally, co -administration of murine CTLA4 Ig, an immunomodulator of T cell activ ation, with the adenovirus protected infected hepatocytes and markedly diminished glomerular beta-galactosidase activity. Collectively, thes e findings suggest that a therapeutic protein can be ''targeted'' to t he renal glomerulus, utilizing the liver as a gene transfer organ.