TY - JOUR
T1 - Prolongation of transgene expression by coexpression of cytokine response modifier A in rodent liver after adenoviral gene transfer
AU - Li, Xiao Kang
AU - Kosuga, Motomichi
AU - Tokieda, Keisuke
AU - Kanaji, Arihiko
AU - Fukuhara, Yasuyuki
AU - Hashimoto, Mitsuhiro
AU - Okabe, Keiko
AU - Yaginuma, Hiroyuki
AU - Yamada, Masao
AU - Suzuki, Seiichi
AU - Okuyama, Torayuki
N1 - Funding Information:
We thank Izumu Saito (Tokyo University) for recombinant adenovirus constructs, and Kyoko Sasaki (National Children's Medical Research Center) and Asami Hirakiyama for technical work. This work was supported in part by Grants for Pediatric Research from the Ministry of Health and Welfare, Japan, and Grants for Research on Health Science Focusing on Drug Innovation from the Japan Health Science Foundation.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
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U2 - 10.1006/mthe.2002.0543
DO - 10.1006/mthe.2002.0543
M3 - Article
C2 - 11863415
AN - SCOPUS:0036197977
SN - 1525-0016
VL - 5
SP - 262
EP - 268
JO - Molecular Therapy
JF - Molecular Therapy
IS - 3
ER -