Blockade of Experimental Atopic Dermatitis via Topical NF-κB Decoy Oligonucleotide

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-κB transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-κB Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-κB Decoy developed for human efficacy demonstrates: (i) efficient NF-κB Decoy penetration in pig skin, (ii) NF-κB 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-κB 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-κB Decoy treatment does not induce skin atrophy. Moreover, topical NF-κB Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-κB Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-κB Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.