The journal of gene medicine · 2012
Intracolonically administered adeno-associated virus-bone morphogenetic protein-7 ameliorates dextran sulphate sodium-induced acute colitis in rats.
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Hao Zhiming, Yang Xiaofei, Lv Yifei, Li Shuang, Purbey Bibek Kumar, Su Houqiang
Аннотация
BACKGROUND: The current treatment of ulcerative colitis (UC) is less than ideal and has room for improvement. Bone morphogenetic protein-7 (BMP-7) exerts a protective effect on experimental UC. Hence, we considered that intracolonically (i.c.) administered adeno-associated virus (AAV) delivering BMP-7 might have therapeutic potential for UC.
METHODS: Recombinant AAV type 2 vectors carrying enhanced green fluorescence protein (AAV-EGFP), LacZ (AAV-LacZ) and BMP-7 (AAV-BMP-7) were generated. Bioluminescence imaging, β-galactosidase assay and western blotting were applied to determine the colonic expression of EGFP, LacZ and BMP-7, respectively, after i.c. administration of the AAVs. Disease activity index (DAI) was observed daily during the 7 days of dextran sulphate sodium (DSS) treatment initiated 4 days after i.c. AAV-BMP-7, AAV-LacZ or phosphate-buffered saline. The colonic pathological morphology, mucosal myeloperoxidase (MPO) activity, malondialdehyde content, superoxide dismutase activity and proliferating cell nuclear antigen were determined at the end of DSS treatment.
RESULTS: When i.c administered to rats, AAV could efficiently transduce the colonic mucosa. Enema with AAV-BMP-7 significantly ameliorated DSS-induced colitis as indicated by reduced DAI, decreased macroscopic and histological scores and declined MPO activity compared to the controls. Furthermore i.c. AAV-BMP-7 significantly prevented oxidant damage and attenuated complementary mucosal cell proliferation in the DSS-treated rat colons.
CONCLUSIONS: Our data demonstrate that i.c. administration of AAV-BMP-7 efficiently mediates the ectopic BMP-7 expression in rat colon and further ameliorates DSS-induced UC in rats, suggesting that i.c. AAV-BMP-7 has the potential to be developed into an alternative therapeutic measure for the treatment of UC.
METHODS: Recombinant AAV type 2 vectors carrying enhanced green fluorescence protein (AAV-EGFP), LacZ (AAV-LacZ) and BMP-7 (AAV-BMP-7) were generated. Bioluminescence imaging, β-galactosidase assay and western blotting were applied to determine the colonic expression of EGFP, LacZ and BMP-7, respectively, after i.c. administration of the AAVs. Disease activity index (DAI) was observed daily during the 7 days of dextran sulphate sodium (DSS) treatment initiated 4 days after i.c. AAV-BMP-7, AAV-LacZ or phosphate-buffered saline. The colonic pathological morphology, mucosal myeloperoxidase (MPO) activity, malondialdehyde content, superoxide dismutase activity and proliferating cell nuclear antigen were determined at the end of DSS treatment.
RESULTS: When i.c administered to rats, AAV could efficiently transduce the colonic mucosa. Enema with AAV-BMP-7 significantly ameliorated DSS-induced colitis as indicated by reduced DAI, decreased macroscopic and histological scores and declined MPO activity compared to the controls. Furthermore i.c. AAV-BMP-7 significantly prevented oxidant damage and attenuated complementary mucosal cell proliferation in the DSS-treated rat colons.
CONCLUSIONS: Our data demonstrate that i.c. administration of AAV-BMP-7 efficiently mediates the ectopic BMP-7 expression in rat colon and further ameliorates DSS-induced UC in rats, suggesting that i.c. AAV-BMP-7 has the potential to be developed into an alternative therapeutic measure for the treatment of UC.