Lentiviral Gene Therapy for Artemis-Deficient SCID

Morton J. Cowan, Jason Yu, Janelle Facchino, Carol Fraser-Browne, Ukina Sanford, Misako Kawahara, Jasmeen Dara, Janel Long-Boyle, Jess Oh, Wendy Chan, Shivali Chag, Lori Broderick, Deepak Chellapandian, Hélène Decaluwe, Catherine Golski, Diana Hu, Caroline Y. Kuo, Holly K. Miller, Aleksandra Petrovic, Robert CurrierJoan F. Hilton, Divya Punwani, Christopher C. Dvorak, Harry L. Malech, R. Scott Mcivor, Jennifer M. Puck

Research output: Contribution to journalArticlepeer-review


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.).

Original languageEnglish (US)
Pages (from-to)2344-2355
Number of pages12
JournalNew England Journal of Medicine
Issue number25
StatePublished - Dec 22 2022


  • Allergy/Immunology
  • Allergy/Immunology General
  • Bone Marrow Transplantation
  • Childhood Diseases
  • Genetics
  • Genetics General
  • Hematology/Oncology
  • Hematology/Oncology General
  • Immunity
  • Immunodeficiency
  • Infectious Disease
  • Infectious Disease General
  • Pediatrics
  • Pediatrics General
  • T-Cells

ASJC Scopus subject areas

  • Medicine(all)


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