- Author
- 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 RH,Bregni M,Marktel S,Valsecchi MG,Rossi P,Ciceri F,Miniero R,Bordignon C,Roncarolo MG
- Title
- Gene therapy for immunodeficiency due to adenosine deaminase deficiency.
- Publication Date
- 1/29/2009
- Pages
- 447-58
- Journal Name
- The New England journal of medicine
- 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, 1.07x10(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.)
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