Non-viral delivery of nuclear factor-κ decoy ameliorates murine inflammatory bowel disease and restores tissue homeostasis

De Vry, Christopher G.; Prasad, Srinivasa; Komuves, Laszlo; Lorenzana, Carlos; Parham, Christi; Le, Tina; Adda, Sarvesh; Hoffman, Jennifer; Kahoud, Nicole; Garlapati, Radhika; Shyamsundar, Radha; Mai, Kim; Jie Zhang; Muchamuel, Tony; Dajee, Maya; Schryver, Brian; McEvoy, Leslie M.; Ehrhardt, Rolf O.
April 2007
Gut;Apr2007, Vol. 56 Issue 4, p524
Academic Journal
Background: Nuclear factor-κB (NF-κB) is a key transcriptional regulator of inflammatory bowel disease (IBD). Aim: To investigate the therapeutic potential of a locally administered "non-viral" nuclear factor-κB decoy (NFκBD) in multiple experimental models of IBD. Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF-κB and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NFκBD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. Results: Intracolonic administration of NFκBD results in the delivery of NFκBD to inflammatory cells and a reduction of NF-κB heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFκBD treatment exhibit a dose-dependent reduction in disease severity and a more rapid recovery to normal body weight, similar to a clinically relevant dose of budesonide. Clinical efficacy was corroborated by considerable reductions in colitis pathology and tissue levels of several pro-inflammatory markers, including tumour necrosis factor α, interleukin 6, interleukin 1β and monocyte chemotactic protein 1. NFκBD also mitigates disease activity in the T helper cell 2-like oxazolone colitis and epithelial injury-related acute dextran sodium sulphate colitis models. Interestingly, restoration of tissue homeostasis is observed in NFκBD-treated animals with the rapid re-emergence of functional goblet cells and a return to normal patterns of cell proliferation in the mucosal epithelium and smooth muscle cell layers. Conclusions: These data support the potential use of "naked" NFκBD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.


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