Recombinant retroviral vectors are attractive tools for achieving sustained
expression of a therapeutic gene in the liver. However, cell division is r
equired for efficient transduction with these vectors. Here we report that
two widely used liver mitogens, triiodothyronin (T3) and cyproterone acetat
e (CPA), enable hepatocyte transduction with recombinant retroviral vectors
delivered in vivo into the bloodstream. Treatment with T3 as well as CPA,
alone or in combination, resulted in an increase in hepatocyte replication
predominantly around the portal tract. The mitogenic activity made it possi
ble to transduce hepatocytes in the same location. Moreover, when administe
red together, the two drugs synergized and the transduction level reached 5
% of hepatocytes. This transduction level is compatible with clinical appli
cations for a number of inherited liver diseases. Since these two compounds
have a long history of safe clinical use, we propose that these liver mito
gens may have potential for clinical application in liver-directed gene the
rapy. (C) 2001 Academic Press.