Intercellular adhesion molecule-1 suppression in skin by topical delivery of anti-sense oligonucleotides.
We topically applied 20 nucleotide phosphorothioate intercellular adhesion molecule-1 anti-sense oligodeoxynucleotide in a cream formulation. It effectively inhibited tumor necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 in human skin transplanted on severe compromised immunodeficient mice. The effects were concentration dependent, sequence specific, and resulted from reduction of intercellular adhesion molecule-1 mRNA levels in the skin. Intravenous administration of the drug did not show pharmacologic effects, probably due to insufficient drug concentrations in skin. Topical delivery, however, produced a rapid and a significantly higher accumulation of oligodeoxynucleotide in the epidermis and dermis. The results strongly suggest that topically applied anti-sense oligonucleotides can be delivered to target sites in the skin and may be of considerable value in the treatment of psoriasis and other inflammatory skin disorders.
Mehta
R C
RC
Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA. rmehta@isisph.com
Stecker
K K
KK
Cooper
S R
SR
Templin
M V
MV
Tsai
Y J
YJ
Condon
T P
TP
Bennett
C F
CF
Hardee
G E
GE
D000287:Administration, Topical; D000818:Animals; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008812:Mice, Hairless; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000737:chemistry* / Q000187:drug effects; D016038:Skin Transplantation / Q000502:physiology
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1