Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells

Nat Med. 2006 Dec;12(12):1397-402. doi: 10.1038/nm1504. Epub 2006 Nov 19.

Abstract

The continuous renewal of human epidermis is sustained by stem cells contained in the epidermal basal layer and in hair follicles. Cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin, mucosal and corneal defects. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epidermolysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient's legs. Engraftment was complete after 8 d. Synthesis and proper assembly of normal levels of functional LAM5 were observed, together with the development of a firmly adherent epidermis that remained stable for the duration of the follow-up (1 year) in the absence of blisters, infections, inflammation or immune response. Retroviral integration site analysis indicated that the regenerated epidermis is maintained by a defined repertoire of transduced stem cells. These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adult
  • Animals
  • Cell Adhesion Molecules / genetics
  • Cells, Cultured
  • Epidermal Cells*
  • Epidermolysis Bullosa, Junctional / therapy*
  • Feasibility Studies
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Male
  • Mice
  • Retroviridae
  • Stem Cell Transplantation*
  • Tissue Engineering / methods

Substances

  • Cell Adhesion Molecules
  • kalinin