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Lentiviral Gene Therapy for Artemis-Deficient SCID.
- Source :
-
The New England journal of medicine [N Engl J Med] 2022 Dec 22; Vol. 387 (25), pp. 2344-2355. - Publication Year :
- 2022
-
Abstract
- 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.<br />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.<br />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.<br />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.).<br /> (Copyright © 2022 Massachusetts Medical Society.)
- Subjects :
- Humans
Infant
Busulfan therapeutic use
Immunoglobulin M
DNA Repair Enzymes deficiency
DNA Repair Enzymes genetics
Antigens, CD34 administration & dosage
Antigens, CD34 immunology
Transplantation, Autologous adverse effects
Transplantation, Autologous methods
Lentivirus
Genetic Vectors administration & dosage
Genetic Vectors adverse effects
Genetic Vectors therapeutic use
T-Lymphocytes immunology
B-Lymphocytes immunology
Genetic Therapy adverse effects
Genetic Therapy methods
Severe Combined Immunodeficiency genetics
Severe Combined Immunodeficiency immunology
Severe Combined Immunodeficiency therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4406
- Volume :
- 387
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- The New England journal of medicine
- Publication Type :
- Academic Journal
- Accession number :
- 36546626
- Full Text :
- https://doi.org/10.1056/NEJMoa2206575