Preclinical corrective gene transfer in Xeroderma pigmentosum human skin stem cells

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dc.contributor.author Warrick, Emilie
dc.contributor.author García Díez, Marta
dc.contributor.author Chagnoleau, Corinne
dc.contributor.author Chevallier, Odile
dc.contributor.author Bergoglio, Valerie
dc.contributor.author Sartori, Daniela
dc.contributor.author Mavilio, Fulvio
dc.contributor.author Angulo, Jaime F.
dc.contributor.author Avril, Marie-Francoise
dc.contributor.author Sarasin, Alain
dc.contributor.author Larcher Laguzzi, Fernando
dc.contributor.author Río, Marcela del
dc.contributor.author Bernerd, Francoise
dc.contributor.author Magnaldo, Thierry
dc.date.accessioned 2014-02-12T16:41:24Z
dc.date.available 2014-02-12T16:41:24Z
dc.date.issued 2012-04
dc.identifier.bibliographicCitation Molecular Therapy, 20(4), 798-807
dc.identifier.issn 1525-0016 (print)
dc.identifier.issn 1525-0024 (electronic)
dc.identifier.uri http://hdl.handle.net/10016/18254
dc.description.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.
dc.description.sponsorship F.L. was supported in part by grants PI081054 from ISCIII and PBIO-0306-2006 from Comunidad de Madrid (CAM). M.D.R. was supported by grant SAF2010-16976 from MICINN. The authors declared no conflict of interest.
dc.format.extent 11
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Academic Press
dc.rights © 2012 The American Society of Gene & Cell Therapy
dc.subject.other Dystrioguc epidermolysis-bullosa
dc.subject.other Human epidermal-keratinocytes
dc.subject.other Nucleotide excision-repair
dc.subject.other Long-term engraftement
dc.subject.other In-vivo assessment
dc.subject.other Group-C protein
dc.subject.other DNA-repair
dc.subject.other Retroviral vectors
dc.subject.other Therapy
dc.subject.other Transduction
dc.title Preclinical corrective gene transfer in Xeroderma pigmentosum human skin stem cells
dc.type article
dc.relation.publisherversion http://dx.doi.og/10.1038/mt.2011.233
dc.subject.eciencia Medicina
dc.identifier.doi 10.1038/mt.2011.233
dc.rights.accessRights openAccess
dc.relation.projectID Comunidad de Madrid. S2010/BMD-2420/CELLCAM
dc.type.version acceptedVersion
dc.identifier.publicationfirstpage 798
dc.identifier.publicationissue 4
dc.identifier.publicationlastpage 807
dc.identifier.publicationtitle Molecular therapy
dc.identifier.publicationvolume 20
dc.identifier.uxxi AR/0000012082
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