Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.
BACKGROUND
X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma (gamma(c)) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gamma(c) gene can restore the immune system in patients with severe combined immunodeficiency.


METHODS
CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the gamma(c) transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer.


RESULTS
No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life.


CONCLUSIONS
Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.
Hacein-Bey-Abina
Salima
S
Laboratoire INSERM, Hôpital Necker Enfants Malades, Paris, France.
Le Deist
Françoise
F
Carlier
Frédérique
F
Bouneaud
Cécile
C
Hue
Christophe
C
De Villartay
Jean-Pierre
JP
Thrasher
Adrian J
AJ
Wulffraat
Nicolas
N
Sorensen
Ricardo
R
Dupuis-Girod
Sophie
S
Fischer
Alain
A
Davies
E Graham
EG
Kuis
Wietse
W
Leiva
Lilly
L
Cavazzana-Calvo
Marina
M
D000906:Antibodies / Q000097:blood; D015703:Antigens, CD / Q000032:analysis; D001854:Bone Marrow Cells; D008040:Genetic Linkage; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016756:Immunoglobulins, Intravenous; D007223:Infant; D007694:Killer Cells, Natural / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D008979:Moloney murine leukemia virus / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D014161:Transduction, Genetic; D019076:Transgenes; D014960:X Chromosome
D000906:Antibodies; D015703:Antigens, CD; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; D018121:Receptors, Cytokine