title: Blockade of experimental atopic dermatitis via topical NF-kappaB decoy oligonucleotide.
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-kappaB transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-kappaB Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-kappaB Decoy developed for human efficacy demonstrates: (i) efficient NF-kappaB Decoy penetration in pig skin, (ii) NF-kappaB 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-kappaB 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-kappaB Decoy treatment does not induce skin atrophy. Moreover, topical NF-kappaB Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-kappaB Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-kappaB Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.
authors.affiliation: Department of Research, Corgentech. Inc., South San Francisco, California, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Dajee
authors.forename: Tony
authors.initials: T
authors.lastname: Muchamuel
authors.forename: Brian
authors.initials: B
authors.lastname: Schryver
authors.forename: Aung
authors.initials: A
authors.lastname: Oo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alleman-Sposeto
authors.forename: Christopher G
authors.initials: CG
authors.lastname: De Vry
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Prasad
authors.forename: Donald
authors.initials: D
authors.lastname: Ruhrmund
authors.forename: Radha
authors.initials: R
authors.lastname: Shyamsundar
authors.forename: Debra
authors.initials: D
authors.lastname: Mutnick
authors.forename: Kim
authors.initials: K
authors.lastname: Mai
authors.forename: Tina
authors.initials: T
authors.lastname: Le
authors.forename: Christi
authors.initials: C
authors.lastname: Parham
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Laszlo
authors.initials: L
authors.lastname: Komuves
authors.forename: Timothy
authors.initials: T
authors.lastname: Colby
authors.forename: Susan
authors.initials: S
authors.lastname: Hudak
authors.forename: Leslie M
authors.initials: LM
authors.lastname: McEvoy
authors.forename: Rolf O
authors.initials: RO
authors.lastname: Ehrhardt
mesh_terms: D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001284:Atrophy; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004431:Ear, External; D004487:Edema / Q000188:drug therapy / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009824:Ointments; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; C468119:NF-kappaB decoy; D009824:Ointments; D009838:Oligodeoxyribonucleotides