Adenovirus-Mediated Hepatic Gene Transfer in Mice: Comparison of Intravascular and Biliary Administration

Abstract

Recombinant adenoviruses have received much attention as a potential vector for gene therapy because of their ability to transduce many cell types with high efficiencies in vivo. After intravenous infusion, the majority of the vector is found in hepatocytes, but vector DNA is found to varying degrees in other tissues. In an attempt to restrict adenovirus-mediated gene transfer to the liver, we developed a microsurgical method that allowed for vector administration directly into the biliary tract of a mouse. We demonstrate that gene transfer was 4- to 10-fold more restricted to the liver after biliary tract infusion than after intravascular infusion. Intravascular infusion of recombinant adenovirus elicits a powerful immune response that limits gene expression and the ability to readminister the vector. Biliary infusion resulted in a slightly lesser immune response as determined by the lower neutralizing antibody titers directed against the vector compared with animals treated by intravascular infusion. There was no difference in the persistence of gene expression, suggesting a similar cell-mediated immune response against the vector containing cells in animals administered vector by either method. As future-generation adenovirus vectors that are safer and less immunogenic become available, the more liver specific gene transfer via the biliary tract may offer advantages over intravenous infusion for hepatic gene therapy.

Reprogramming liver-stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors

“…20,25 For this reason, we deliberately chose to examine the short-term gene expression profiles between Pdx1-and Pdx1-VP16-expressing WB cells at day-6 after lentiviral transduction. Our results indicated that expression of Pdx1-VP16 short-term is more efficient than Pdx1 in initiating the process of the liver-to-endocrine transdifferentiation (eg NKx2.2 activation) and inducing insulin II gene expression (Figure 3).…”

Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

“…24 After intravenous infusion, the majority of the adenoviral vector can ultimately be found in the liver but delivery of recombinant adenovirus in this manner elicits a powerful systemic immune response that limits gene expression and the ability to re-administer the viral vector. [27][28][29] Manipulation of the host immune response with potent immune suppressants is one strategy employed to eliminate the toxic effects of adenoviral vectors during liverdirected gene transfer. 6,7 However, there is growing evidence that the presence of proinflammatory or immune mediators in the liver may be integral to liver regeneration following an acute insult.…”

An interaction between penton base and αv integrins plays a minimal role in adenovirus-mediated gene transfer to hepatocytes in vitro and in vivo

“…For example, we are aware of no studies that have investigated this in hepatocytes, a cell that is readily infected by adenovirus in vitro [6][7][8] and in vivo. [1][2][3][4][5] Our data suggest that the interaction between adenovirus fiber and a fiber receptor are important for infection. This conclusion is consistent with studies carried out in a number of easily infected cell lines.…”

“…For example, after intravenous injection of recombinant adenovirus, gene transfer to the liver is most efficient. [1][2][3][4][5] Gene transfer to hepatocytes is also efficient in vitro. [6][7][8] However, the mechanisms by which adenoviruses infect hepatocytes has received little attention.…”