Primary immune deficiencies (PID) are inherited disorders of the adaptive and innate immune system marked by severe infections, autoimmunity and high risk of cancer. Treatment entails hematopoietic stem cell (HSC) transplantation from allogeneic donors, however in the absence of an HLA compatible donor, HSCT outcome is limited by delayed or suboptimal reconstitution and complications. SCID-X1 and ADA-SCID have been successfully treated with autologous gene corrected HSC, however, associated with safety issues inherent to first generation retroviral vectors. This project utilizes genetically modified HSC and their descendants as immunotherapeutic cells to build a healthy immune system in PID patients, and is carried out by clinical centres, scientists and industrial partners pioneering in the field of advanced therapies and aiming at broad clinical application of safe cell-based therapeutic products. Multicentre phase I/II clinical trials for SCID-X1 and WAS are ready to start. Disease targeted technology to cure ADA-SCID, V(D)J recombination defects and CGD by gene corrected HSC and novel approaches in IPEX and HLH to gene modify already committed cells will be investigated. Based on rigorous preclinical efficacy and toxicology evaluation, flanked by basic studies aimed at improving HSC homing capacity and thymic epithelium regeneration, new clinical trials will be implemented. The consortium will establish a technology platform to implement, harmonize and run controlled, standardized multicentre preclinical studies using state-of-the-art advanced therapy. Strict observance of good practice quality guidelines and regulation of medicinal product development will be ensured. The successful completion of the project will be instrumental to accomplish and broaden clinical application of medicinal products able to rebuild and modulate the immune system with an anticipated impact that extends beyond PID to acquired immune disorders, allogeneic HSCT and cancer treatment.