¹Department of Research, Corgentech. Inc., South San Francisco, California, USA

Correspondence: Dr Rolf O. Ehrhardt, Department of Research, Corgentech. Inc., 650 Gateway Blvd., South San Francisco, California, USA. E-mail: ehrhardt@corgentech.com

²Both these authors contributed equally to this work.

Received 23 December 2005; Revised 2 February 2006; Accepted 24 February 2006; Published online 20 April 2006.

Abstract

Atopic dermatitis (AD) is a common chronic skin inflammatory disease. Long-term use of topical corticosteroids in skin inflammation poses risks of systemic and local side effects. The NF-B transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-B Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-B Decoy developed for human efficacy demonstrates: (i) efficient NF-B Decoy penetration in pig skin, (ii) NF-B Decoy nuclear localization in keratinocytes and key immune cells, and (iii) potent "steroid-like" efficacy in a chronic dust-mite antigen skin inflammation treatment model. NF-B Decoy exerts its anti-inflammatory action through the effective inhibition of essential regulators of inflammation and by induction of apoptosis of key immune cells. Unlike betamethasone valerate (BMV), long-term NF-B Decoy treatment does not induce skin atrophy. Moreover, topical NF-B Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-B Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-B Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.