title: Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice.
abstract: Recombinant adenoviruses (Ad) are among the most extensively used vectors for liver gene transfer. One of the major limitations for the clinical application of these vectors is the inflammatory immune response associated with systemic administration of high dose of virus. We evaluated the effect of Ad administration route on the inflammatory immune response and liver transgene expression. We compared direct intrahepatic injection (IH) with the systemic administration via tail vein (IV). IH injection of Ad resulted in a lower inflammatory response and a higher transgene expression. When a relatively low dose of virus was used, IV administration resulted in no detectable protein expression but production of proinflammatory cytokines. In contrast, IH administration induced high levels of transgene expression and no inflammation, although we detected a transient hypertransaminemia, which fully resolved within days. Furthermore, IH injection resulted in a faster protein expression being more intense at the site of injection, whereas IV administration caused slower but diffuse liver expression. IH injection also reduced the spreading of the virus to other organs. Independently of the route, depletion of Kupffer cells significantly enhanced the transduction efficiency of Ad. This effect was stronger when using IV injection, indicating that IH injection partially overcomes Kupffer cell phagocytic activity. Moreover, the antitumor efficacy of high-capacity-Ad encoding murine interleukin-12 (IL-12) was significantly greater when the vector was administered by IH injection than when given IV. In conclusion, IH injection of adenovirus represents a safe and efficient administration route for clinical applications of gene therapy targeting the liver.
authors.affiliation: Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Crettaz
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.forename: L
authors.initials: L
authors.lastname: Ochoa-Callejero
authors.forename: Laura
authors.initials: L
authors.lastname: Ochoa
authors.forename: Vijay
authors.initials: V
authors.lastname: Shankar
authors.forename: Miguel
authors.initials: M
authors.lastname: Barajas
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Rubén
authors.initials: R
authors.lastname: Hernández-Alcoceba
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D018664:Interleukin-12 / Q000378:metabolism; D007728:Kupffer Cells / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D018664:Interleukin-12