Background We investigated the long-term outcome of gene therapyfor severe combined immunodeficiency (SCID) due to the lackof adenosine deaminase (ADA), a fatal disorder of purine metabolismand immunodeficiency.
Methods We infused autologous CD34+ bone marrow cells transducedwith a retroviral vector containing the ADA gene into 10 childrenwith SCID due to ADA deficiency who lacked an HLA-identicalsibling donor, after nonmyeloablative conditioning with busulfan.Enzyme-replacement therapy was not given after infusion of thecells.
Results All patients are alive after a median follow-up of 4.0years (range, 1.8 to 8.0). Transduced hematopoietic stem cellshave stably engrafted and differentiated into myeloid cellscontaining 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-replacementtherapy, their blood cells continue to express ADA, and theyhave no signs of defective detoxification of purine metabolites.Nine patients had immune reconstitution with increases in T-cellcounts (median count at 3 years, 1.07x109 per liter) and normalizationof T-cell function. In the five patients in whom intravenousimmune globulin replacement was discontinued, antigen-specificantibody responses were elicited after exposure to vaccinesor viral antigens. Effective protection against infections andimprovement in physical development made a normal lifestylepossible. Serious adverse events included prolonged neutropenia(in two patients), hypertension (in one), central-venous-catheter–relatedinfections (in two), Epstein–Barr virus reactivation (inone), and autoimmune hepatitis (in one).
Conclusions Gene therapy, combined with reduced-intensity conditioning,is a safe and effective treatment for SCID in patients withADA deficiency. (ClinicalTrials.gov numbers, NCT00598481
[ClinicalTrials.gov]
andNCT00599781
[ClinicalTrials.gov]
.)
Source Information
From the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) (A.A., F.C., U.B., B.C., L.C., S. Scaramuzza, G.A., M.M., I.B., S.M., M.-G.R.), University of Milan-Bicocca (S.G., M.G.V.), Ospedale San Giuseppe (M.B.), San Raffaele Scientific Institute (F.C.), Università Vita–Salute San Raffaele (C.B., M.-G.R.), and MolMed (C.B.) — all in Milan; Tor Vergata University (A.A., P.R.) and Children's Hospital Bambino Gesù (P.R.) — both in Rome; University of Siena, Siena (A.T., F.C.); and University of Turin, Turin (R.M.) — all in Italy; Immunologische Tagesklinik, Vienna, Austria (M.E.); Hadassah University Hospital, Jerusalem, Israel (M.A., S. Slavin); King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (H.A.-M., A.A.G.); Hôpital Universitaire des Enfants Reine Fabiola–Université Libre de Bruxelles, Brussels (A.F.); University Children's Hospital, Bern, Switzerland (A.D.); Children's Hospital, Harvard Medical School, Boston (L.N.); Universitäts-Kinderklinik München, Munich, Germany (U.W.); and Duke University Medical Center, Durham, NC (R.H.B.).
Address reprint requests to Dr. Roncarolo at HSR-TIGET, Via Olgettina 58, 20132 Milan, Italy, or at m.roncarolo{at}hsr.it.
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