Recombinant adenovirus vectors for cytokine gene therapy in mice.
BACKGROUND
Adenoviruses have several specific features useful for gene therapy. They infect various lineages of cells irrespective of cell cycle status. However, the exact mechanism of their infection and in vivo kinetics as a gene expression vector have not been elucidated.


OBJECTIVE
Using adenovirus vectors expressing marker genes, we examined the infectivity of these vectors (including cellular and tissue tropism), the duration and intensity of transgene expression, and the side effects.


METHODS
Various cells were infected with adenovirus expressing LacZ gene at various doses, and beta-galactosidase activity was measured and compared in relation with dose, time course, and cellular vitronectin receptor. Mice were injected with adenoviruses expressing LacZ, luciferase and GM-CSF, and in vivo gene expression was examined.


RESULTS
Adenovirus infection induced viral dose-dependent transgene expression that persisted for 2 weeks. Adherent cells were infected much more efficiently than nonadherent cells, probably because the former expressed much higher levels of the vitronectin receptor, one of the main receptors for adenovirus. Studies performed in mice with luciferase-expressing adenovirus revealed that the liver was the main target organ after intravenous injection and showed that the intravenous route was superior to other routes with regard to transgene expression. After intravenous injection of adenovirus expressing human GM-CSF, there was a transient and dose-dependent increase in the serum level of this cytokine. Administration of adenovirus expressing mouse GM-CSF enhanced hematopoiesis in the spleen and bone marrow.


CONCLUSIONS
These results indicated that adenoviruses can be used for in vivo cytokine gene therapy but suggested the necessity of taking into consideration the route of administration, the duration of transgene expression, the toxic dose, and host immune reactions.
D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D019556:COS Cells / Q000821:virology; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007231:Infant, Newborn; D007275:Injections, Intravenous; D019169:Jurkat Cells / Q000821:virology; D007763:Lac Operon / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019030:Receptors, Vitronectin / Q000235:genetics; D013997:Time Factors; D014018:Tissue Distribution