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 psoriasi s. Stimulation of epidermal keratinocytes by insulin-like growth factor I ( IGF-I) is essential for cell division, and increased sensitivity to IGF-I m ay occur in psoriasis. We hypothesized that inhibition of IGF-I receptor ex pression in the psoriasis lesion would reverse psoriatic epidermal hyperpla sia by stowing the rate of keratinocyte cell division. Here we report the u se of C5-propynyl-dU,dC-phosphorothioate antisense oligonucleotides to inhi bit IGF-I receptor expression in keratinocytes. We identified several inhib itory 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, caus ed a dramatic normalization of the hyperplastic epidermis. The findings ind icate that IGF-I receptor stimulation is a rate-limiting step in psoriatic epidermal hyperplasia and that IGF-I receptor targeting by cutaneous admini stration of antisense oligonucleotides forms the basis of a potential new p soriasis therapy.