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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Lentiviral Gene Therapy for Artemis-Deficient SCID
New England Journal of Medicine, Volume 387, No. 25, Year 2022
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Description
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.). © 2022 Massachusetts Medical Society.
Authors & Co-Authors
Cowan, Morton J.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
United States, San Francisco
University of California, San Francisco
Dara, Jasmeen S.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
United States, San Francisco
University of California, San Francisco
Long-Boyle, Janel Renee
United States, San Francisco
Ucsf Benioff Children‘s Hospital
United States, San Francisco
University of California, San Francisco
Kuo, Caroline Y.
United States, San Diego
Rady Children's Hospital
Currier, Robert J.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
Hilton, Joan F.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
Dvorak, Christopher C.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
United States, San Francisco
University of California, San Francisco
Malech, Harry L.
Unknown Affiliation
Puck, Jennifer M.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
United States, San Francisco
University of California, San Francisco
Statistics
Citations: 18
Authors: 9
Affiliations: 11
Identifiers
Doi:
10.1056/NEJMoa2206575
ISSN:
00284793
Research Areas
Genetics And Genomics
Health System And Policy
Maternal And Child Health