Efficacy of gene therapy for X-linked severe combined immunodeficiency.
BACKGROUND
The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain.


METHODS
The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up.


RESULTS
Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health.


CONCLUSIONS
After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)
Hacein-Bey-Abina
Salima
S
Department of Biotherapy, Necker-Enfants Malades Hospital, Paris, France. salima.hacein-bey@nck.ap-hop-paris.fr
Hauer
Julia
J
Lim
Annick
A
Picard
Capucine
C
Wang
Gary P
GP
Berry
Charles C
CC
Martinache
Chantal
C
Rieux-Laucat
Frédéric
F
Latour
Sylvain
S
Belohradsky
Bernd H
BH
Leiva
Lily
L
Sorensen
Ricardo
R
Debré
Marianne
M
Casanova
Jean Laurent
JL
Blanche
Stephane
S
Durandy
Anne
A
Bushman
Frederic D
FD
Fischer
Alain
A
Cavazzana-Calvo
Marina
M
D018952:Antigens, CD34; D001402:B-Lymphocytes / Q000276:immunology; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics*; D007694:Killer Cells, Natural / Q000502:physiology; D018655:Lymphocyte Count; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
D018952:Antigens, CD34; C507941:IL2RG protein, human; D007136:Immunoglobulins; D053631:Interleukin Receptor Common gamma Subunit