Uwe Wintergerst, Pier Luca Rossi, Alina Ferster, Roberto Miniero, Maria Grazia Roncarolo, Filippo Carlucci, Massimiliano Mirolo, Grazia Andolfi, Andrea Duppenthaler, Federica Cattaneo, Sarah Marktel, Rebecca H. Buckley, Fabio Ciceri, Hamoud Al-Mousa, Claudio Bordignon, Luigi D. Notarangelo, Abdulaziz Al Ghonaium, Alessandro Aiuti, Ulrike Benninghoff, Antonella Tabucchi, Stefania Galimberti, Marco Bregni, Memet Aker, Martha M. Eibl, Luciano Callegaro, Samantha Scaramuzza, Maria Grazia Valsecchi, Barbara Cassani, Immacolata Brigida, Shimon Slavin, 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, Al 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, Aiuti, Alessandro, AL MOUSA, H, AL GHONAIUM, A, BUCKLEY R., H, Valsecchi, M. G., Ciceri, Fabio, Bordignon, Claudio, and Roncarolo, MARIA GRAZIA
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. RI rossi, paolo/D-6504-2012; galimberti, stefania/H-2594-2012 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, 1.07x10(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.) BackgroundWe investigated the long-term outcome of gene therapy for severe combined immunodeficiency(SCID) due to the lack of adenosine deaminase (ADA), a fatal disorderof purine metabolism and immunodeficiency.MethodsWe infused autologous CD34+ bone marrow cells transduced with a retroviral vectorcontaining the ADA gene into 10 children with SCID due to ADA deficiency wholacked an HLA-identical sibling donor, after nonmyeloablative conditioning withbusulfan. Enzyme-replacement therapy was not given after infusion of the cells.ResultsAll patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transducedhematopoietic stem cells have stably engrafted and differentiated into myeloidcells 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 patientsdo not require enzyme-replacement therapy, their blood cells continue to expressADA, and they have no signs of defective detoxification of purine metabolites. Ninepatients had immune reconstitution with increases in T-cell counts (median countat 3 years, 1.07×109 per liter) and normalization of T-cell function. In the five patientsin whom intravenous immune globulin replacement was discontinued, antigenspecificantibody responses were elicited after exposure to vaccines or viral antigens.Effective protection against infections and improvement in physical development madea normal lifestyle possible. Serious adverse events included prolonged neutropenia(in two patients), hypertension (in one), central-venous-catheter–related infections (intwo), Epstein–Barr virus reactivation (in one), and autoimmune hepatitis (in one).ConclusionsGene therapy, combined with reduced-intensity conditioning, is a safe and effectivetreatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers,NCT00598481 and NCT00599781.)