Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides

Christopher J. Wraight, Paul J. White, Sandra C. McKean, Rhys D. Fogarty, Daryl J. Venables, Ingrid J. Liepe, Stephanie R. Edmondson, George A. Werther

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)521-526
Number of pages6
JournalNature Biotechnology
Volume18
Issue number5
DOIs
Publication statusPublished or Issued - May 2000

Keywords

  • Antisense oligonucleotides
  • Hyperproliferation
  • IGF I receptor
  • Keratinocytes
  • Psoriasis

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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