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Gene Therapy for Inherited Skin Adhesion Disorders

Final Report Summary - GT-SKIN (Gene Therapy for Inherited Skin Adhesion Disorders)

The objective of the GT-SKIN project was the development and pre-clinical evaluation of genome editing as the next-generation gene therapy technology. Gene editing aims at correcting genetic defects by the use of engineered nucleases targeted to specific DNA sequences, and exploiting the natural DNA repair machinery to introduce deletions or edit natural sequences by template-directed homologous recombination. We designed and tested vectors and non-viral delivery system to introduce genes or RNA molecules encoding Zn-finger nucleases (ZFNs) or the CRISPR/Cas9 editing machinery together with homologous recombination templates to introduce targeted gene deletion or gene correction in different types of human stem cells. The research aimed of providing a safer alternative to classical gene replacement for the therapy of recessive skin adhesion defects (epidermolysis bullosa) and red blood cell disorders (sickle-cell disease). A parallel, basic research program applied 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 epidermal and hematopoietic stem cells. Over five years, the project helped to develop next-generation technology for safer and more efficacious gene therapy, and to establish a knowledge base for a better utilization of stem cells in clinical medicine.