Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides.
Epidermal hyperplasia is a key feature of the common skin disorder psoriasis. Stimulation of epidermal keratinocytes by insulin-like growth factor I (IGF-I) is essential for cell division, and increased sensitivity to IGF-I may occur in psoriasis. We hypothesized that inhibition of IGF-I receptor expression in the psoriasis lesion would reverse psoriatic epidermal hyperplasia by slowing the rate of keratinocyte cell division. Here we report the use of C5-propynyl-dU,dC-phosphorothioate antisense oligonucleotides to inhibit IGF-I receptor expression in keratinocytes. We identified several inhibitory antisense oligonucleotides and demonstrated IGF-I receptor inhibition in vitro through an mRNA targeting mechanism. Repeated injection of these oligonucleotides into human psoriasis lesions, grafted onto nude mice, caused a dramatic normalization of the hyperplastic epidermis. The findings indicate that IGF-I receptor stimulation is a rate-limiting step in psoriatic epidermal hyperplasia and that IGF-I receptor targeting by cutaneous administration of antisense oligonucleotides forms the basis of a potential new psoriasis therapy.
Wraight
C J
CJ
Centre for Hormone Research, Royal Children's Hospital, Parkville, Victoria 3052, Australia. wraight@cryptic.rch.unimelb.edu.au
White
P J
PJ
McKean
S C
SC
Fogarty
R D
RD
Venables
D J
DJ
Liepe
I J
IJ
Edmondson
S R
SR
Werther
G A
GA
D000818:Animals; D004817:Epidermis / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D007271:Injections, Intradermal; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy*; D012333:RNA, Messenger / Q000302:isolation & purification; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000235:genetics*; D016038:Skin Transplantation; D014183:Transplantation, Heterologous
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1