Objective Epidermolysis bullosa (EB) is a family of severe skin adhesion defects characterized by disfiguring blistering, infections, visual impairment, and a high risk of cancer. We showed through pre-clinical and clinical investigation that transplantation of genetically corrected epithelia leads to long-term functional correction of EB. The current vectors, however, integrate in an uncontrolled fashion in the human genome, a cause of genotoxicity and potentially severe adverse events. The objective of this project is the development and pre-clinical evaluation of new gene targeting and gene correction technology, aimed at integrating therapeutic transgenes at specific loci or at correcting genetic defects by homologous recombination. Epidermal stem cells (EpSCs) and EB are ideal targets for the design and development of such technology, which is expected to have an impact on gene therapy of many other genetic diseases. We will design and test novel viral vectors for homologous recombination based on site-specific integrases and Zn-finger nucleases, and non-viral vectors for integrating large genes and complex regulatory sequences based on vertebrate transposons. All vectors will be tested in repopulating human EpSCs in vitro and in vivo, in a pre-clinical model of xenotransplantation of human skin on immunodeficient mice. A parallel, basic research program will aim at applying existing and novel genomic approaches to the definition of transcription factors, regulatory regions and gene expression programs involved in self renewal, commitment and differentiation of EpSCs. The anticipated output of the project is the development of next-generation technology for gene transfer, and the establishment of a knowledge base for a better utilization of EpSCs in gene therapy. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologymedical and health sciencesclinical medicinetransplantationnatural sciencesbiological sciencesgeneticsgenomes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution ASSOCIATION GENETHON EU contribution € 2 210 000,00 Address RUE DE L INTERNATIONALE 1 BIS 91002 Evry France See on map Region Ile-de-France Ile-de-France Essonne Activity type Research Organisations Principal investigator Fulvio Mavilio (Prof.) Administrative Contact Jean-Philippe Marin (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all ASSOCIATION GENETHON France EU contribution € 2 210 000,00 Address RUE DE L INTERNATIONALE 1 BIS 91002 Evry See on map Region Ile-de-France Ile-de-France Essonne Activity type Research Organisations Principal investigator Fulvio Mavilio (Prof.) Administrative Contact Jean-Philippe Marin (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data