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 hormone (hGH) in mice after intravenous administration of a retroviral vector encoding the protein as a model system for clotting factor VIII gene therapy. Such treatment results in a brief burst of high-level expression followed by lower level sustained expression of the hGH in the circulation. The major targets for transduction in the mouse are liver and spleen. Such direct transduction (i.e., without surgical or chemical induction of cell division) requires vector at high titer (>/=10(8) cfu/ml) and is dose dependent. Transduction efficiency decreases with increasing age of the recipient. Nevertheless, long-term expression in adults is observed after administration of vector as a split dose on 2 consecutive days. We also show that anti-vector immune responses may enhance long-term expression and 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.
McCormack
J E
JE
Chiron Corporation Center for Gene Therapy, 11055 Roselle Street, San Diego, California 92121, USA.
Edwards
W
W
Sensintaffer
J
J
Lillegren
L
L
Kozloski
M
M
Brumm
D
D
Karavodin
L
L
Jolly
D J
DJ
Greengard
J
J
D000367:Age Factors; D000818:Animals; D000941:Antigens / Q000235:genetics*; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005167:Factor VII / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D019382:Human Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012190:Retroviridae / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes
D000941:Antigens; C042580:factor VII clotting antigen; D019382:Human Growth Hormone; D003520:Cyclophosphamide; D005167:Factor VII