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Gene Therapy for Inherited Skin Adhesion Disorders (GT-SKIN)
Start date: Dec 1, 2011, End date: May 31, 2017 PROJECT  FINISHED 

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.

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