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

This study is a prospective, non-randomized, open-label, two-centre phase I/II intervention study designed to treat children up to 24 months of age with RAG1-deficient SCID with an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The study involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in five patients with RAG1-deficient SCID.

Severe combined immunodeficiency (SCID) is a genetically heterogeneous life-threatening disease characterized by severely impaired T cell development with or without impaired natural killer (NK) and B cell development or function depending on the genetic defect. Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) represent about 20% of all types of SCID. SCID is a paediatric emergency since it leads to severe and recurrent infections often in combination with protracted diarrhoea and failure to thrive. When left untreated, it is usually fatal within the first year of life. Currently, the only curative treatment option for RAG-deficient SCID is allogeneic hematopoietic stem cell transplantation (HSCT). Despite improvements in HSCT in recent years, this treatment is associated with serious potential complications like graft-versus-host disease which results in an unfavourable outcome, particularly in patients who lack a human leukocyte antigen (HLA)-matched donor. In recent years, gene therapy based on transplantation of autologous gene-corrected hematopoietic stem cells (HSC) has evolved as an effective and safe therapeutic option for X-linked and ADA-deficient forms of SCID. We have recently demonstrated that gene therapy using lentiviral (LV) self-inactivating (SIN) vectors expressing codon-optimized human RAG1 in a mouse model for RAG1-deficient SCID effectively restores T and B cell development and function. In this phase I/II explorative intervention study feasibility, safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral blood or bone marrow cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an human leukocyte antigen (HLA)-matched donor.

Inclusion Criteria: 1. RAG1-deficient SCID as confirmed by genetic analysis 2. Peripheral blood T cells \< 300/μL and/or naïve T cells \< 1/μL 3. Age \< 2 years 4. Age at least 8 weeks by the time of busulfan and fludarabine administration 5. Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor) 6. Signed informed consent (parental or guardian) 7. Able to return to the study centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review Exclusion Criteria: 1. Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor) 2. RAG1 deficiency with peripheral blood T cells \> 300/μL and/or naïve T cells \> 1/μL 3. Omenn syndrome 4. Previous allogeneic HSCT 5. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below): 1. Mechanical ventilation 2. Shortening fraction on echocardiogram \<25% 3. Renal failure defined as dialysis dependence 4. Uncontrolled seizure disorder 6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of trans-duced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits. 7. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection