Blockade of experimental atopic dermatitis via topical NF-kappaB 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-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.
Dajee
Maya
M
Department of Research, Corgentech. Inc., South San Francisco, California, USA.
Muchamuel
Tony
T
Schryver
Brian
B
Oo
Aung
A
Alleman-Sposeto
Jennifer
J
De Vry
Christopher G
CG
Prasad
Srinivasa
S
Ruhrmund
Donald
D
Shyamsundar
Radha
R
Mutnick
Debra
D
Mai
Kim
K
Le
Tina
T
Parham
Christi
C
Zhang
Jie
J
Komuves
Laszlo
L
Colby
Timothy
T
Hudak
Susan
S
McEvoy
Leslie M
LM
Ehrhardt
Rolf O
RO
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
D007166:Immunosuppressive Agents; C468119:NF-kappaB decoy; D009824:Ointments; D009838:Oligodeoxyribonucleotides