Alessandro Aiuti, M.D., Ph.D., Federica Cattaneo, M.D., Stefania Galimberti, Ph.D., Ulrike Benninghoff, M.D., Barbara Cassani, Ph.D., Luciano Callegaro, R.N., Samantha Scaramuzza, Ph.D., Grazia Andolfi, Massimiliano Mirolo, B.Sc., Immacolata Brigida, B.Sc., Antonella Tabucchi, Ph.D., Filippo Carlucci, Ph.D., Martha Eibl, M.D., Memet Aker, M.D., Shimon Slavin, M.D., Hamoud Al-Mousa, M.D., Abdulaziz Al Ghonaium, M.D., Alina Ferster, M.D., Andrea Duppenthaler, M.D., Luigi Notarangelo, M.D., Uwe Wintergerst, M.D., Rebecca H. Buckley, M.D., Marco Bregni, M.D., Sarah Marktel, M.D., Maria Grazia Valsecchi, Ph.D., Paolo Rossi, M.D., Fabio Ciceri, M.D., Roberto Miniero, M.D., Claudio Bordignon, M.D., and Maria-Grazia Roncarolo, M.D.
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, 1.07x109 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 [ClinicalTrials.gov] and NCT00599781 [ClinicalTrials.gov] .)