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Non-viral delivery of nuclear factor-κB decoy ameliorates murine inflammatory bowel disease and restores tissue homeostasis
  1. Christopher G De Vry,
  2. Srinivasa Prasad,
  3. Laszlo Komuves,
  4. Carlos Lorenzana,
  5. Christi Parham,
  6. Tina Le,
  7. Sarvesh Adda,
  8. Jennifer Hoffman,
  9. Nicole Kahoud,
  10. Radhika Garlapati,
  11. Radha Shyamsundar,
  12. Kim Mai,
  13. Jie Zhang,
  14. Tony Muchamuel,
  15. Maya Dajee,
  16. Brian Schryver,
  17. Leslie M McEvoy,
  18. Rolf O Ehrhardt
  1. Department of Research, Corgentech, Inc, South San Francisco, California, USA
  1. Correspondence to:
    Dr R O Ehrhardt
    Clinical Science, Intermune, Inc, 3280 Bayshore Blvd, Brisbane, CA 94005, USA; rehrhardt{at}intermune.com

Abstract

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.

  • DAI, Disease Activity Index
  • DSS, dextran sodium sulphate
  • EMSAs, electromobility shift assays
  • HEX, hexachlorofluorescein
  • IBD, inflammatory bowel disease
  • ICAM, intercellular adhesion molecule
  • ITF, intestinal trefoil factor
  • MCP, monocyte chemotactic protein
  • MPO, myeloperoxidase
  • NF-κB, nuclear factor-κB
  • NFκBD, nuclear factor-κB decoy
  • ODN, phosphorothioated NFκBD oligonucleotide
  • PCR, polymerase chain rection
  • Th1, T helper cell 1
  • Th2, T helper cell 2
  • TNBS, trinitrobenzene sulphonic acid

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Footnotes

  • Published Online First 1 September 2006

  • Competing interests: None.

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