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Corrective gene transfer in the human skin disorder lamellar ichthyosis

Nature Medicine volume 2, pages 1263–1267 (1996)Cite this article

Abstract

Lamellar ichthyosis (LI) is a disfiguring skin disease characterized by abnormal epidermal differentiation and defective cutaneous barrier function1,2. LI has been associated with loss of keratinocyte transglutaminase 1 (Tgase1)3,4, an enzyme believed necessary for normal formation of the cornified epidermal barrier. Using LI as a prototype for therapeutic cutaneous gene delivery, we have used the human skin/immunodeficient mouse xenograft model to correct the molecular, histologic and functional abnormalities of LI patient skin in vivo. We have used Tgase1–deficient primary keratinocytes from LI patients combined with high–efficiency transfer of functional Tgase1 to regenerate engineered human LI epidermis on immunodeficient mice. Engineered LI epidermis displayed normal Tgase1 expression in vivo, unlike unengineered LI epidermis where Tgase1 was absent. Epidermal architecture was also normalized by Tgase1 restoration, as was expression of the epidermal differentiation marker filaggrin. Engineered LI skin demonstrated restoration of cutaneous barrier function measures to levels seen in epidermis regenerated by keratinocytes from patients with normal skin, indicating functional correction in vivo of the proposed primary pathophysiologic defect in LI. These results confirm a major role for Tgase1 in epidermal differentiation and demonstrate a potential future approach to therapeutic gene delivery in human skin.

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Authors and Affiliations

  1. Veterans Affairs Palo Alto Health Care System, Palo Alto VA Medical Center, 3801 Miranda Avenue, Palo Alto, California, 94304, USA

    Keith A. Choate & Paul A. Khavari

  2. Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Bums Institute Research Center, One Kendall Square, Building 1400, Cambridge, Massachusetts, 02139, USA

    Dan A. Medalie & Jeff R. Morgan

  3. Department of Dermatology, P204, MSLS, Stanford University School of Medicine, Stanford, California, 94305, USA

    Paul A. Khavari

Authors
  1. Keith A. Choate
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  2. Dan A. Medalie
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  3. Jeff R. Morgan
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  4. Paul A. Khavari
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Choate, K., Medalie, D., Morgan, J. et al. Corrective gene transfer in the human skin disorder lamellar ichthyosis. Nat Med 2, 1263–1267 (1996). https://doi.org/10.1038/nm1196-1263

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