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Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice
Author(s) -
Crettaz Julien,
Berraondo Pedro,
Mauleón Itsaso,
Ochoa Laura,
Shankar Vijay,
Barajas Miguel,
van Rooijen Nico,
Kochanek Stefan,
Qian Cheng,
Prieto Jesús,
HernándezAlcoceba Rubén,
GonzálezAseguinolaza Gloria
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21292
Subject(s) - transgene , genetic enhancement , systemic administration , inflammation , adenoviridae , proinflammatory cytokine , immune system , medicine , gene expression , viral vector , immunology , pharmacology , biology , recombinant dna , in vivo , gene , biochemistry , microbiology and biotechnology
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. (H EPATOLOGY 2006.)