Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07 x 10(sup 9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). Conclusions: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) N Engl J Med 2009;360:447-58.

Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. NEW ENGLAND JOURNAL OF MEDICINE, 360(5), 447-458 [10.1056/NEJMoa0805817].

Gene therapy for immunodeficiency due to adenosine deaminase deficiency

AIUTI, ALESSANDRO;ROSSI, PAOLO;
2009

Abstract

Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07 x 10(sup 9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). Conclusions: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) N Engl J Med 2009;360:447-58.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/38 - Pediatria Generale e Specialistica
English
Con Impact Factor ISI
adenosine deaminase; busulfan; diphtheria toxin; Haemophilus influenzae type b vaccine; immunoglobulin; pegademase; pertussis toxin; retrovirus vector; tetanus toxoid; virus antigen; CD34 antigen; adenosine deaminase deficiency; antibody response; antigen specificity; area under the curve; article; autoimmune hepatitis; autoimmune thrombocytopenia; bone marrow cell; catheter infection; cell function; central venous catheter; child; clinical article; clinical trial; controlled clinical trial; controlled study; donor; drug efficacy; drug safety; enzyme replacement; Epstein Barr virus; female; follow up; genetic transduction; hematopoietic stem cell; HLA system; human; hypertension; immune reconstitution inflammatory syndrome; infant; infection prevention; lymphocyte count; lymphoid cell; male; neutropenia; newborn; nonmyeloablative conditioning; outcome assessment; physical development; preschool child; priority journal; protein expression; severe combined immunodeficiency; sibling; T lymphocyte; thrombocytopenia; viral gene therapy; virus reactivation; gene therapy; gene vector; genetics; hematopoietic stem cell transplantation; immunology; immunosuppressive treatment; multicenter study; multimodality cancer therapy; phase 1 clinical trial; phase 2 clinical trial; Retrovirus; Adenosine Deaminase; Antigens, CD34; Bone Marrow Cells; Child, Preschool; Combined Modality Therapy; Follow-Up Studies; Gene Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphocyte Count; Retroviridae; Severe Combined Immunodeficiency; Transduction, Genetic; Transplantation Conditioning
Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. NEW ENGLAND JOURNAL OF MEDICINE, 360(5), 447-458 [10.1056/NEJMoa0805817].
Aiuti, A; Cattaneo, F; Galimberti, S; Benninghoff, U; Cassani, B; Callegaro, L; Scaramuzza, S; Andolfi, G; Mirolo, M; Brigida, I; Tabucchi, A; Carlucci, F; Eibl, M; Aker, M; Slavin, S; Al Mousa, H; Ghonaium, A; Ferster, A; Duppenthaler, A; Notarangelo, L; Wintergerst, U; Buckley, R; Bregni, M; Marktel, S; Valsecchi, M; Rossi, P; Ciceri, F; Miniero, R; Bordignon, C; Roncarolo, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/42792
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