Gene therapy for immunodeficiency due to adenosine deaminase deficiency.
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.)
Aiuti
Alessandro
A
San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
Cattaneo
Federica
F
Galimberti
Stefania
S
Benninghoff
Ulrike
U
Cassani
Barbara
B
Callegaro
Luciano
L
Scaramuzza
Samantha
S
Andolfi
Grazia
G
Mirolo
Massimiliano
M
Brigida
Immacolata
I
Tabucchi
Antonella
A
Carlucci
Filippo
F
Eibl
Martha
M
Aker
Memet
M
Slavin
Shimon
S
Al-Mousa
Hamoud
H
Al Ghonaium
Abdulaziz
A
Ferster
Alina
A
Duppenthaler
Andrea
A
Notarangelo
Luigi
L
Wintergerst
Uwe
U
Buckley
Rebecca H
RH
Bregni
Marco
M
Marktel
Sarah
S
Valsecchi
Maria Grazia
MG
Rossi
Paolo
P
Ciceri
Fabio
F
Miniero
Roberto
R
Bordignon
Claudio
C
Roncarolo
Maria-Grazia
MG
D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics*; D018952:Antigens, CD34 / Q000235:genetics*; D001854:Bone Marrow Cells / Q000276:immunology; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005500:Follow-Up Studies; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D018655:Lymphocyte Count; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic; D019172:Transplantation Conditioning
D018952:Antigens, CD34; D000243:Adenosine Deaminase