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

被引:44
作者
De Vry, Christopher G. [1 ]
Prasad, Srinivasa [1 ]
Komuves, Laszlo [1 ]
Lorenzana, Carlos [1 ]
Parham, Christi [1 ]
Le, Tina [1 ]
Adda, Sarvesh [1 ]
Hoffman, Jennifer [1 ]
Kahoud, Nicole [1 ]
Garlapati, Radhika [1 ]
Shyamsundar, Radha [1 ]
Mai, Kim [1 ]
Zhang, Jie [1 ]
Muchamuel, Tony [1 ]
Dajee, Maya [1 ]
Schryver, Brian [1 ]
McEvoy, Leslie M. [1 ]
Ehrhardt, Rolf O. [1 ]
机构
[1] Intermune Inc, Clin Sci, 3280 Bayshore Blvd, Brisbane, CA USA
关键词
D O I
10.1136/gut.2006.096487
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: Nuclear factor-kappa B (NF-kappa B) is a key transcriptional regulator of inflammatory bowel disease (IBD). Aim: To investigate the therapeutic potential of a locally administered "non-viral'' nuclear factor-kappa B decoy (NF kappa BD) in multiple experimental models of IBD. Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF kappa B and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NF kappa BD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. Results: Intracolonic administration of NFkBD results in the delivery of NF kappa BD to inflammatory cells and a reduction of NF-kappa B heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFk kappa BD 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 proinflammatory markers, including tumour necrosis factor alpha, interleukin delta, interleukin 1 beta and monocyte chemotactic protein 1. NF kappa BD 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 NF kappa BD-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'' NF kappa BD 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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页码:524 / 533
页数:10
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