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 (>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.

Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells / Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F.; Avril, Marie Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 20:(2012), pp. 798-807. [10.1038/mt.2011.233]

Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells

MAVILIO, Fulvio;
2012

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 (>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.
2012
20
798
807
Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells / Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F.; Avril, Marie Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 20:(2012), pp. 798-807. [10.1038/mt.2011.233]
Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F.; Avril, Marie Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1074776
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