Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID

This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The trial involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in up to 10 patients with RAG1-deficient SCID. Patients will be regularly monitored for 5 years after infusion. Follow up as part of routine clinical care for post-transplant patients will be annual after this, for at least 15 years after IMP infusion.

Inclusion Criteria: 1. RAG1-deficient SCID as confirmed by genetic analysis 2. Peripheral blood CD3+T cells \< 300/μL 3. Absence of peripheral blood naïve CD4+ T cells 4. Age \< 2 years 5. Age at least 8 weeks by the time of busulfan and fludarabine administration 6. Lack of an available HLA-identical sibling/family donor 7. Signed informed consent (parental or guardian) 8. Able to return to the local HSCT centre for follow-up (per protocol) during the 5-year trial and up to at least 15-year long-term follow-up after IMP administration Exclusion Criteria: 1. Omenn syndrome 2. Previous allogeneic HSCT 3. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below): 1. Mechanical ventilation 2. Shortening fraction on echocardiogram \