Gene therapy for immunodeficiency due to adenosine deaminase deficiency

Alessandro Aiuti, Federica Cattaneo, Stefania Galimberti, Ulrike Benninghoff, Barbara Cassani, Luciano Callegaro, Samantha Scaramuzza, Grazia Andolfi, Massimiliano Mirolo, Immacolata Brigida, Antonella Tabucchi, Filippo Carlucci, Martha Eibl, Memet Aker, Shimon Slavin, Hamoud Al-Mousa, Abdulaziz Al Ghonaium, Alina Ferster, Andrea Duppenthaler, Luigi Notarangelo & 10 others Uwe Wintergerst, Rebecca H. Buckley, Marco Bregni, Sarah Marktel, Maria Grazia Valsecchi, Paolo Rossi, Fabio Ciceri, Roberto Miniero, Claudio Bordignon, Maria Grazia Roncarolo

Research output: Contribution to journalArticle

692 Citations (Scopus)

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, 1.07×10 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.)

Original languageEnglish
Pages (from-to)447-458
Number of pages12
JournalNew England Journal of Medicine
Volume360
Issue number5
DOIs
Publication statusPublished - 29 Jan 2009
Externally publishedYes

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Genetic Therapy
Adenosine Deaminase
Enzyme Replacement Therapy
Severe Combined Immunodeficiency
T-Lymphocytes
Catheter-Related Infections
Busulfan
Autoimmune Hepatitis
Central Venous Catheters
Viral Antigens
Intravenous Immunoglobulins
Myeloid Cells
Hematopoietic Stem Cells
Neutropenia
Human Herpesvirus 4
Bone Marrow Cells
Antibody Formation
Severe combined immunodeficiency due to adenosine deaminase deficiency
Life Style
Siblings

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., ... Roncarolo, M. G. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. New England Journal of Medicine, 360(5), 447-458. https://doi.org/10.1056/NEJMoa0805817

Gene therapy for immunodeficiency due to adenosine deaminase deficiency. / Aiuti, Alessandro; Cattaneo, Federica; Galimberti, Stefania; Benninghoff, Ulrike; Cassani, Barbara; Callegaro, Luciano; Scaramuzza, Samantha; Andolfi, Grazia; Mirolo, Massimiliano; Brigida, Immacolata; Tabucchi, Antonella; Carlucci, Filippo; Eibl, Martha; Aker, Memet; Slavin, Shimon; Al-Mousa, Hamoud; Ghonaium, Abdulaziz Al; Ferster, Alina; Duppenthaler, Andrea; Notarangelo, Luigi; Wintergerst, Uwe; Buckley, Rebecca H.; Bregni, Marco; Marktel, Sarah; Valsecchi, Maria Grazia; Rossi, Paolo; Ciceri, Fabio; Miniero, Roberto; Bordignon, Claudio; Roncarolo, Maria Grazia.

In: New England Journal of Medicine, Vol. 360, No. 5, 29.01.2009, p. 447-458.

Research output: Contribution to journalArticle

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, AA, Ferster, A, Duppenthaler, A, Notarangelo, L, Wintergerst, U, Buckley, RH, Bregni, M, Marktel, S, Valsecchi, MG, Rossi, P, Ciceri, F, Miniero, R, Bordignon, C & Roncarolo, MG 2009, 'Gene therapy for immunodeficiency due to adenosine deaminase deficiency', New England Journal of Medicine, vol. 360, no. 5, pp. 447-458. https://doi.org/10.1056/NEJMoa0805817
Aiuti, Alessandro ; Cattaneo, Federica ; Galimberti, Stefania ; Benninghoff, Ulrike ; Cassani, Barbara ; Callegaro, Luciano ; Scaramuzza, Samantha ; Andolfi, Grazia ; Mirolo, Massimiliano ; Brigida, Immacolata ; Tabucchi, Antonella ; Carlucci, Filippo ; Eibl, Martha ; Aker, Memet ; Slavin, Shimon ; Al-Mousa, Hamoud ; Ghonaium, Abdulaziz Al ; Ferster, Alina ; Duppenthaler, Andrea ; Notarangelo, Luigi ; Wintergerst, Uwe ; Buckley, Rebecca H. ; Bregni, Marco ; Marktel, Sarah ; Valsecchi, Maria Grazia ; Rossi, Paolo ; Ciceri, Fabio ; Miniero, Roberto ; Bordignon, Claudio ; Roncarolo, Maria Grazia. / Gene therapy for immunodeficiency due to adenosine deaminase deficiency. In: New England Journal of Medicine. 2009 ; Vol. 360, No. 5. pp. 447-458.
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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, 1.07×10 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.)",
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AU - Aiuti, Alessandro

AU - Cattaneo, Federica

AU - Galimberti, Stefania

AU - Benninghoff, Ulrike

AU - Cassani, Barbara

AU - Callegaro, Luciano

AU - Scaramuzza, Samantha

AU - Andolfi, Grazia

AU - Mirolo, Massimiliano

AU - Brigida, Immacolata

AU - Tabucchi, Antonella

AU - Carlucci, Filippo

AU - Eibl, Martha

AU - Aker, Memet

AU - Slavin, Shimon

AU - Al-Mousa, Hamoud

AU - Ghonaium, Abdulaziz Al

AU - Ferster, Alina

AU - Duppenthaler, Andrea

AU - Notarangelo, Luigi

AU - Wintergerst, Uwe

AU - Buckley, Rebecca H.

AU - Bregni, Marco

AU - Marktel, Sarah

AU - Valsecchi, Maria Grazia

AU - Rossi, Paolo

AU - Ciceri, Fabio

AU - Miniero, Roberto

AU - Bordignon, Claudio

AU - Roncarolo, Maria Grazia

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N2 - 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, 1.07×10 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.)

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