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

Nature Biotechnology volume 18, pages 521–526 (2000)Cite this article

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.

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Figure 1: Reduction in IGF-I receptor mRNA in HaCaT cells following treatment with antisense oligonucleotides.
Figure 2: Reduction in total cellular IGF-I receptor protein following antisense oligonucleotide treatment.
Figure 3: Reduction in IGF-I receptor numbers on the keratinocyte cell surface after antisense oligonucleotide treatment.
Figure 4: Reduction in keratinocyte cell number following antisense oligonucleotide treatment.
Figure 5: Reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides Grafted psoriasis lesions were injected with IGF-I receptor-specific antisense oligonucleotides, a random-sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analyzed histologically.
Figure 6: Reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides.

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Acknowledgements

This work was supported by the AusIndustry Syndicated Research and Development scheme and the Royal Children's Hospital Research Institute. We gratefully acknowledge the help and advice from Denys Fortune, Kathryn Wraight, David Randerson, Richard Wagner, David Atkins, and the late Peter Cable.

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Authors and Affiliations

  1. Centre for Hormone Research, Royal Children's Hospital , Parkville, 3052, Victoria, Australia

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

  2. Department of Pharmaceutical Biology and Pharmacology Victorian College of Pharmacy, Monash University, Parkville, 3052, Victoria, Australia

    Paul J. White

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Correspondence to Christopher J. Wraight.

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Wraight, C., White, P., McKean, S. et al. Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides. Nat Biotechnol 18, 521–526 (2000). https://doi.org/10.1038/75382

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