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

  • End date
    Apr 1, 2024
  • participants needed
  • sponsor
    Leiden University Medical Center
Updated on 4 April 2021


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.

Condition Severe Combined Immunodeficiency Due to Complete RAG1 and/or RAG2 Deficiency, Severe Combined Immunodeficiency Due to Complete RAG1 and/or RAG2 Deficiency, Severe Combined Immunodeficiency Due to RAG1 Deficiency
Treatment Gene therapy, Gene therapy
Clinical Study IdentifierNCT04797260
SponsorLeiden University Medical Center
Last Modified on4 April 2021


Yes No Not Sure

Inclusion Criteria

RAG1-deficient SCID as confirmed by genetic analysis
Peripheral blood T cells < 300/L and/or nave T cells < 1/L
Age < 2 years
Age at least 8 weeks by the time of busulfan and fludarabine administration
Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
Signed informed consent (parental or guardian)
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

Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
RAG1 deficiency with peripheral blood T cells > 300/L and/or nave T cells > 1/L
Omenn syndrome
Previous allogeneic HSCT
Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below)
Mechanical ventilation
Shortening fraction on echocardiogram <25%
Renal failure defined as dialysis dependence
Uncontrolled seizure disorder
any other medical condition which, in the opinion of the treating physician, would interfere with the good conduction of the clinical trial (e.g. contraindications for stem cell harvest or administration of conditioning medication)
Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
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