Intradermal injection of lentiviral vectors corrects regenerated human dystrophic epidermolysis bullosa skin tissue in vivo

David T. Woodley, Douglas R. Keene, Tom Atha, Yi Huang, Ramin Ram, Noriyuki Kasahara, Mei Chen

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechanobullous disorders caused by mutations in the gene, COL7A1, that codes for type VII, (anchoring fibril), collagen, which is critical for epidermal-dermal adherence. Most gene therapy approaches have been ex vivo, involving cell culture and culture graft transplantation, which is logistically difficult. To develop a more simplified approach, we engineered a self-inactivating lentiviral vector expressing human type VII collagen and injected this vector intradermally into hairless, immunodeficient mice and into a human DEB composite skin equivalent grafted onto immunodeficient mice. In both situations, the vector transduced dermal cells, which in turn synthesized and exported type VII collagen into the extracellular space. Remarkably, the type VII collagen selectively adhered to and incorporated into the basement membrane zone (BMZ) between the dermis and the epidermis, where it formed anchoring fibril structures. In the case of the DEB skin equivalent, the newly expressed type VII collagen reversed the DEB phenotype characterized by poor epidermal-dermal adherence and anchoring fibril defects. A single lentiviral vector injection provided stable type VII collagen at the BMZ for at least 3 months. These data demonstrate efficient and long-term type VII collagen gene transfer in vivo using direct intradermal injection of an engineered lentiviral vector.

Original languageEnglish (US)
Pages (from-to)318-326
Number of pages9
JournalMolecular Therapy
Volume10
Issue number2
DOIs
StatePublished - Aug 1 2004

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Keywords

  • Anchoring fibril
  • Basement membrane zone
  • Gene therapy
  • Lentivirus
  • Type VII colagen

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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