Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency.

被引:718
作者
Aiuti, Alessandro [1 ,7 ]
Cattaneo, Federica [1 ,4 ]
Galimberti, Stefania [2 ]
Benninghoff, Ulrike [1 ]
Cassani, Barbara [1 ]
Callegaro, Luciano [1 ]
Scaramuzza, Samantha [1 ]
Andolfi, Grazia [1 ]
Mirolo, Massimiliano [1 ]
Brigida, Immacolata [1 ]
Tabucchi, Antonella [9 ]
Carlucci, Filippo [9 ]
Eibl, Martha [11 ]
Aker, Memet [12 ]
Slavin, Shimon [12 ]
Al-Mousa, Hamoud [13 ]
Al Ghonaium, Abdulaziz [13 ]
Ferster, Alina [14 ]
Duppenthaler, Andrea [15 ]
Notarangelo, Luigi [16 ]
Wintergerst, Uwe [17 ]
Buckley, Rebecca H. [18 ]
Bregni, Marco [3 ]
Marktel, Sarah [1 ]
Valsecchi, Maria Grazia [2 ]
Rossi, Paolo [7 ,8 ]
Ciceri, Fabio
Miniero, Roberto [10 ]
Bordignon, Claudio [5 ,6 ]
Roncarolo, Maria-Grazia [1 ,5 ]
机构
[1] Univ Milano Bicocca, HSR TIGET, I-20132 Milan, Italy
[2] Univ Milano Bicocca, Milan, Italy
[3] Osped San Giuseppe, Milan, Italy
[4] Ist Sci San Raffaele, I-20132 Milan, Italy
[5] Univ Vita Salute San Raffaele, Milan, Italy
[6] MolMed, Milan, Italy
[7] Univ Roma Tor Vergata, Rome, Italy
[8] Childrens Hosp Bambino Gesu, Rome, Italy
[9] Univ Siena, I-53100 Siena, Italy
[10] Univ Turin, Turin, Italy
[11] Immunol Tagesklin, Vienna, Austria
[12] Hadassah Univ Hosp, IL-91120 Jerusalem, Israel
[13] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia
[14] Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Brussels, Belgium
[15] Univ Childrens Hosp, Bern, Switzerland
[16] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA
[17] Univ Kinderklin Munchen, Munich, Germany
[18] Duke Univ, Med Ctr, Durham, NC USA
关键词
STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; BLOOD-LYMPHOCYTES; THYMIC OUTPUT; ADA; RECONSTITUTION; ACTIVATION; EXPRESSION; CHILDHOOD; LEADS;
D O I
10.1056/NEJMoa0805817
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:447 / 458
页数:12
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