Lentiviral Gene Therapy for Artemis-Deficient SCID

N Engl J Med. 2022 Dec 22;387(25):2344-2355. doi: 10.1056/NEJMoa2206575.


Background: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation.

Methods: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months.

Results: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report.

Conclusions: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / administration & dosage
  • Antigens, CD34 / immunology
  • B-Lymphocytes / immunology
  • Busulfan / therapeutic use
  • DNA Repair Enzymes / deficiency
  • DNA Repair Enzymes / genetics
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / therapeutic use
  • Humans
  • Immunoglobulin M
  • Infant
  • Lentivirus
  • Severe Combined Immunodeficiency* / genetics
  • Severe Combined Immunodeficiency* / immunology
  • Severe Combined Immunodeficiency* / therapy
  • T-Lymphocytes / immunology
  • Transplantation, Autologous / adverse effects
  • Transplantation, Autologous / methods


  • Busulfan
  • Immunoglobulin M
  • DNA Repair Enzymes
  • DCLRE1C protein, human
  • Antigens, CD34

Associated data

  • ClinicalTrials.gov/NCT03538899