Factors affecting long-term expression of a secreted transgene product after intravenous administration of a retroviral vector

We have studied parameters affecting in vivo expression of human growth hor mone (hGH) in mice after intravenous administration of a retroviral vector encoding the protein as a model system for clotting factor VIII gene therap y. Such treatment results in a brief burst of high-level expression followe d by lower level sustained expression of the hGH in the circulation. The ma jor targets for transduction in the mouse are liver and spleen. Such direct transduction (i.e., without surgical or chemical induction of cell divisio n) requires vector at high titer (greater than or equal to 10(8) cfu/ml) an d is dose dependent. Transduction efficiency decreases with increasing age of the recipient. Nevertheless, longterm expression in adults is observed a fter administration of vector as a split dose on 2 consecutive days. We als o show that anti-vector immune responses may enhance long-term expression a nd that both anti-vector and anti-transgene immunity can be modulated. This work provides a framework for the rational development of means to enhance the efficiency of retroviral vectors for use in clinical gene replacement therapy.