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Lentiviral Gene Therapy for Artemis-Deficient SCID.
Cowan, Morton J; Yu, Jason; Facchino, Janelle; Fraser-Browne, Carol; Sanford, Ukina; Kawahara, Misako; Dara, Jasmeen; Long-Boyle, Janel; Oh, Jess; Chan, Wendy; Chag, Shivali; Broderick, Lori; Chellapandian, Deepak; Decaluwe, Hélène; Golski, Catherine; Hu, Diana; Kuo, Caroline Y; Miller, Holly K; Petrovic, Aleksandra; Currier, Robert; Hilton, Joan F; Punwani, Divya; Dvorak, Christopher C; Malech, Harry L; McIvor, R Scott; Puck, Jennifer M.
Afiliación
  • Cowan MJ; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Yu J; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Facchino J; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Fraser-Browne C; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Sanford U; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Kawahara M; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Dara J; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Long-Boyle J; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Oh J; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Chan W; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Chag S; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Broderick L; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Chellapandian D; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Decaluwe H; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Golski C; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Hu D; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Kuo CY; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Miller HK; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Petrovic A; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Currier R; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Hilton JF; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Punwani D; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Dvorak CC; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Malech HL; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • McIvor RS; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
  • Puck JM; From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San
N Engl J Med ; 387(25): 2344-2355, 2022 12 22.
Article en En | MEDLINE | ID: mdl-36546626
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.

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 ß 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.).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Inmunodeficiencia Combinada Grave Límite: Humans / Infant Idioma: En Revista: N Engl J Med Año: 2022 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Inmunodeficiencia Combinada Grave Límite: Humans / Infant Idioma: En Revista: N Engl J Med Año: 2022 Tipo del documento: Article