Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.
BACKGROUND
X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector.


METHODS
Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery.


RESULTS
All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes.


CONCLUSIONS
Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.
Gaspar
H Bobby
HB
Molecular Immunology Unit, Institute of Child Health, University College London, London, UK.
Parsley
Kathryn L
KL
Howe
Steven
S
King
Doug
D
Gilmour
Kimberly C
KC
Sinclair
Joanna
J
Brouns
Gaby
G
Schmidt
Manfred
M
Von Kalle
Christof
C
Barington
Torben
T
Jakobsen
Marianne A
MA
Christensen
Hans O
HO
Al Ghonaium
Abdulaziz
A
White
Harry N
HN
Smith
John L
JL
Levinsky
Roland J
RJ
Ali
Robin R
RR
Kinnon
Christine
C
Thrasher
Adrian J
AJ
D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D017988:Gammaretrovirus; D018014:Gene Transfer Techniques; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007109:Immunity; D007136:Immunoglobulins / Q000097:blood; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009154:Mutation; D020395:Receptors, Interleukin-7 / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D018952:Antigens, CD34; C507941:IL2RG protein, human; D007136:Immunoglobulins; D053631:Interleukin Receptor Common gamma Subunit; D020395:Receptors, Interleukin-7