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Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells.

  • Emilie Warrick
  • Marta Garcia
  • Corinne Chagnoleau
  • Odile Chevallier
  • Valérie Bergoglio
  • Daniela Sartori
  • Fulvio Mavilio
  • Jaime F Angulo
  • Marie-Françoise Avril
  • Alain Sarasin
  • Fernando Larcher
  • Marcela Del Rio
  • Françoise Bernerd
  • Thierry Magnaldo
DOI: 10.1038/mt.2011.233


Xeroderma pigmentosum (XP) is a devastating disease associated with dramatic skin cancer proneness. XP cells are deficient in nucleotide excision repair (NER) of bulky DNA adducts including ultraviolet (UV)-induced mutagenic lesions. Approaches of corrective gene transfer in NER-deficient keratinocyte stem cells hold great hope for the long-term treatment of XP patients. To face this challenge, we developed a retrovirus-based strategy to safely transduce the wild-type XPC gene into clonogenic human primary XP-C keratinocytes. De novo expression of XPC was maintained in both mass population and derived independent candidate stem cells (holoclones) after more than 130 population doublings (PD) in culture upon serial propagation ( & gt;10(40) cells). Analyses of retrovirus integration sequences in isolated keratinocyte stem cells suggested the absence of adverse effects such as oncogenic activation or clonal expansion. Furthermore, corrected XP-C keratinocytes exhibited full NER capacity as well as normal features of epidermal differentiation in both organotypic skin cultures and in a preclinical murine model of human skin regeneration in vivo. The achievement of a long-term genetic correction of XP-C epidermal stem cells constitutes the first preclinical model of ex vivo gene therapy for XP-C patients.

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