Prolongation of transgene expression by coexpression of cytokine response modifier A in rodent liver after adenoviral gene transfer

Xiao Kang Li, Motomichi Kosuga, Keisuke Tokieda, Arihiko Kanaji, Yasuyuki Fukuhara, Mitsuhiro Hashimoto, Keiko Okabe, Hiroyuki Yaginuma, Masao Yamada, Seiichi Suzuki, Torayuki Okuyama

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The short duration of expression of the transgenes is a major barrier to the clinical application of adenovirus-mediated gene therapy for hepatic enzyme deficiencies. Previous reports show that Fas-mediated apoptosis has a pivotal role in the rapid elimination of adenovirus-infected hepatocytes. After considering this result and our recent observation that murine hepatocytes can be protected from Fas-mediated apoptosis by expressing cytokine response modifier A (CrmA) in vivo, we hypothesized that CrmA coexpression could also prevent adenovirus-infected hepatocytes from rapid elimination and that this would make prolonged transgene expression achievable in vivo. To examine this, mice with congenital deficiency of lysosomal β-glucuronidase (GUSB) were infected with recombinant adenoviruses expressing both CrmA and GUSB, and the duration of transgene expression was evaluated. The serum GUSB activity in the mice injected with a recombinant adenovirus expressing GUSB only became undetectable 60 days after the injection, whereas higher than normal GUSB activity was observed for at least 120 days in mice injected with adenoviruses expressing both GUSB and CrmA. Furthermore, we showed that exogenous CrmA expression could prevent the adenovirus-infected hepatocytes from cell death induced by cytotoxic T lymphocytes in vitro. These observations indicate that transgene expression after administration of E1-deleted adenovirus is prolonged by coexpression of the anti-apoptotic protein CrmA.

Original languageEnglish
Pages (from-to)262-268
Number of pages7
JournalMolecular Therapy
Volume5
Issue number3
DOIs
Publication statusPublished - 2002 Jan 1

    Fingerprint

Keywords

  • Adenovirus
  • Cytokine response modifier A
  • Gene therapy
  • β-glucuronidase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Li, X. K., Kosuga, M., Tokieda, K., Kanaji, A., Fukuhara, Y., Hashimoto, M., Okabe, K., Yaginuma, H., Yamada, M., Suzuki, S., & Okuyama, T. (2002). Prolongation of transgene expression by coexpression of cytokine response modifier A in rodent liver after adenoviral gene transfer. Molecular Therapy, 5(3), 262-268. https://doi.org/10.1006/mthe.2002.0543