Cyclooxygenase-2 silencing for the treatment of colitis: a combined in vivo strategy based on RNA interference and engineered Escherichia coli.
Nonpathogenic-invasive Escherichia coli (InvColi) bacteria are suitable for genetic transfer into mammalian cells and may act as a vehicle for RNA Interference (RNAi) in vivo. Cyclooxygenase-2 (COX-2) is overexpressed in ulcerative colitis (UC) and Crohn's disease (CD), two inflammatory conditions of the colon and small intestine grouped as inflammatory bowel disease (IBD). We engineered InvColi strains for anti-COX-2 RNAi (InvColi(shCOX2)), aiming to investigate the in vivo feasibility of a novel COX-2 silencing strategy in a murine model of colitis induced by dextran sulfate sodium (DSS). Enema administrations of InvColi(shCOX2) in DSS-treated mice led to COX-2 downregulation, colonic mucosa preservation, reduced colitis disease activity index (DAI) and increased mice survival. Moreover, DSS/InvColi(shCOX2)-treated mice showed lower levels of circulating pro-inflammatory cytokines and a reduced colitis-associated shift of gut microbiota. Considering its effectiveness and safety, we propose our InvColi(shCOX2) strategy as a promising tool for molecular therapy in intestinal inflammatory diseases.
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Enzo
E
Spisni
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Maria C
MC
Valerii
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Luigia
L
De Fazio
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Elena
E
Cavazza
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Francesca
F
Borsetti
1] Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy [2] Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
Annamaria
A
Sgromo
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Marco
M
Candela
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Manuela
M
Centanni
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Fernando
F
Rizello
Department of Biological, Geological and Environmental Sciences, Biology Unit, University of Bologna, Bologna, Italy.
Antonio
A
Strillacci
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D015870:Gene Expression; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2