title: Prolongation of transgene expression by coexpression of cytokine response modifier a in rodent liver after adenoviral gene transfer.
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 beta-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 antiapoptotic protein CrmA.
authors.affiliation: Department of Experimental Surgery, National Children's Medical Research Center, Tokyo 154-8509, Japan.
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
authors.forename: Motomichi
authors.initials: M
authors.lastname: Kosuga
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tokieda
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanaji
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukuhara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Okabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yaginuma
authors.forename: Masao
authors.initials: M
authors.lastname: Yamada
authors.forename: Seiichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Torayuki
authors.initials: T
authors.lastname: Okuyama
mesh_terms: D000256:Adenoviridae; D000818:Animals; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008099:Liver / Q000502:physiology*; D051379:Mice; D015843:Serpins / Q000096:biosynthesis / Q000235:genetics*; D019076:Transgenes / Q000235:genetics* / Q000502:physiology; D014764:Viral Proteins
chemical_list: D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor