The chimeric cytokine Hyper-IL-6 enhances the efficiency of lentiviral gene transfer in hepatocytes both in vitro and in vivo

Abstract

Lentiviral vectors have been used for gene transfer into the liver but their ability to efficiently transduce quiescent hepatocytes remains controversial. Lentivirus-mediated gene transfer is more efficient in cycling cells. We determine the effect of H-IL6 in the lentiviral transduction. The lentiviral vector was used to transduce HepG2 cells and mice liver cells, previously treated with H-IL6. The highest transduction level was observed in HepG2 cells treated with 30 ng/mL H-IL6 and in the mice that received 4 microg H-IL6. Our results suggest that H-IL6 is an inducer of lentiviral gene transfer into the liver cells without any toxicity.

Transient Increase in Intrahepatic Pressure Mediates Successful Treatment of the Gunn Rat with Reduced Doses of Lentiviral Vector

“…However, in these studies lentiviral transduction of hepatocytes was relatively inefficient and the majority of transduced liver cells were of nonparenchymal origin. The induction of liver regeneration, triggered by a two-thirds partial hepatectomy and/or the administration of a hepatic mitogen, was shown to dramatically stimulate hepatocyte transduction in adult mice (Park et al, 2000;Ohashi et al, 2002;Picanco-Castro et al, 2008). Consistent with these data, an impressive increase in hepatocyte transduction was observed without host manipulation when lentiviral vector was injected into young mice (3-4 weeks old), in which the liver is still actively growing, as compared with injection into older mice (Park et al, 2003).…”

Hydroxyethyl starch-based preservation solutions enhance gene therapy vector delivery under hypothermic conditions

“…Although lentiviral vectors are capable of transducing mitotically quiescent cells,18, 19 the levels attainable in vivo are generally lower than those in vitro,20 possibly because of lentiviral vectors needing some level of cell cycling in vivo to effectively transduce hepatocytes 21. Given this, it is not surprising that we saw lower transductions in both primary mouse hepatocytes (Fig.…”

“…7B). The trends were similar, in that UW gave better transductions than other solutions used, indicating that UW could be a viable transduction agent for transfer of a genetic therapy to liver grafts during perfusion, although in order to increase transductions to therapeutic levels, additives may be required such as hyper‐interleukin‐620 or growth factors such as hepatocyte growth factor or epidermal growth factor 22…”

Priming of Hepatocytes Enhances In Vivo Liver Transduction with Lentiviral Vectors in Adult Mice

“…Most of the methods that have been described so far to enhance lentiviral transduction (partial hepatectomy, treatment with potentially carcinogenic chemical compounds) are not fully compatible with a clinical application. Recently, a 10-fold increase in liver transduction was achieved in mice that were pretreated with a chimeric hyper-interleukin-6 cytokine (Picanço-Castro et al, 2008). This cytokine is known to participate in the initiation of liver regeneration as a priming agent, but is devoid of the potency to cause full cell replication (Webber et al, 1994).…”

“…Induction of cell proliferation by mitogens or by partial hepatectomy dramatically improves liver transduction (Park et al, 2000;Ohashi et al, 2002;Picanço-Castro et al, 2008). In mice, using lentiviral vectors carrying LacZ cDNA, there was a nearly 30-fold increase in X-Gal-positive hepatocytes in hepatectomized animals, resulting in up to 60% hepatocyte transduction, compared with less than 3% in nonhepatectomized controls (Park et al, 2000).…”