We have developed the tools and experimental models and have provided the proof of principle that gene modified autologous haematopoietic stem cells can restore a complete immunological system in vivo in a particular form of SCID. We are pursuing these efforts applying this strategy to several other diseases : two lentivirus protocols for X-linked adrenoleukodystrophy, Thalassemia and sickle cell disease, are developed in our Clinical Investigation Centre. In 2010, we plan to initiate two other gene therapy trials for two primary immunodeficiencies (SCID-X1 and Wiskott-Aldrich syndrome). Our expertise in translational medicine has now been used to transfer into clinics a new gene therapy protocol for a devastating inherited skin disease : dystrophic epidermolysis bullosa. To complement these approaches, we optimize HLA-mismatched haematopoietic stem cell transplantation (HSCT). They are an important therapeutic option for children with primary immunodeficiencies but the delayed reconstitution of the T-cell compartment following T-cell depleted HSCT remains a major clinical concern thus drastically limiting its broader clinical application. In order to speed-up the immunological reconstitution in this setting, we try to pre-clinically develop a new approach able to generate a large quantity of T-cellular precursors from a fraction of the donor CD34+ stem cells shortly cultured on Notch delta 4 ligand. This strategy could ideally provide the recipient with a pool of diverse T-cells within the first month after transplantation conferring T-cellular immunity before de novo thymopoiesis takes place.The results obtained with this procedure are so important that we think to extend its use to the transduction of HSC for the gene therapy trials.