Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa

Mei Chen, Noriyuki Kasahara, Douglas R. Keene, Lawrence Chan, Warren K. Hoeffier, Deborah Finlay, Maria Barcova, Paula M. Cannon, Constance Mazurek, David T. Woodley

Research output: Contribution to journalArticle

151 Scopus citations

Abstract

Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous disorders caused by mutations in the human type VII collagen gene (COL7A1). Individuals with DEB lack type VII collagen and anchoring fibrils, structures that attach epidermis and dermis. The current lack of treatment for DEB is an impetus to develop gene therapy strategies that efficiently transfer and stably express genes delivered to skin cells in vivo. In this study, we delivered and expressed full-length type VII collagen using a self-inactivating minimal lentivirus-based vector. Transduction of lentiviral vectors containing the COL7A1 transgene into recessive DEB (RDEB) keratinocytes and fibroblasts (in which type VII collagen was absent) resulted in persistent synthesis and secretion of type VII collagen. Unlike RDEB parent cells, the gene-corrected cells had normal morphology, proliferative potential, matrix attachment and motility. We used these gene-corrected cells to regenerate human skin on immune-deficient mice. Human skin regenerated by gene-corrected RDEB cells had restored expression of type VII collagen and formation of anchoring fibrils at the dermal-epidermal junction in vivo. These studies demonstrate that it is possible to restore type VII collagen gene expression in RDEB skin in vivo.

Original languageEnglish (US)
Pages (from-to)670-675
Number of pages6
JournalNature genetics
Volume32
Issue number4
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Chen, M., Kasahara, N., Keene, D. R., Chan, L., Hoeffier, W. K., Finlay, D., Barcova, M., Cannon, P. M., Mazurek, C., & Woodley, D. T. (2002). Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa. Nature genetics, 32(4), 670-675. https://doi.org/10.1038/ng1041