共 33 条
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.
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页码:447 / 458
页数:12
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