Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells - Institut Gustave Roussy Access content directly
Journal Articles Molecular Therapy Year : 2012

Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells

Abstract

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 (>1040 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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Dates and versions

hal-02325743 , version 1 (09-11-2023)

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Attribution - NonCommercial - NoDerivatives

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Emilie Warrick, Marta Garcia, Corinne Chagnoleau, Odile Chevallier, Valérie Bergoglio, et al.. Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells. Molecular Therapy, 2012, 20 (4), pp.798-807. ⟨10.1038/mt.2011.233⟩. ⟨hal-02325743⟩
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