Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector

X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor γchain(γc), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is...

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Bibliographic Details
Published in:The Lancet (British edition) 2004-12, Vol.364 (9452), p.2181-2187
Main Authors: Gaspar, H Bobby, Parsley, Kathryn L, Howe, Steven, King, Doug, Gilmour, Kimberly C, Sinclair, Joanna, Brouns, Gaby, Schmidt, Manfred, Von Kalle, Christof, Barington, Torben, Jakobsen, Marianne A, Christensen, Hans O, Al Ghonaium, Abdulaziz, White, Harry N, Smith, John L, Levinsky, Roland J, Ali, Robin R, Kinnon, Christine, Thrasher, Adrian J
Format: Article
Language:English
Subjects:
Antigens
Antigens, CD34 - analysis
Autografts
Autoimmune diseases
Biological and medical sciences
Bone marrow
Bone Marrow Cells - immunology
Bone Marrow Transplantation
CD34 antigen
Chemotherapy
Child, Preschool
Children
Clinical trials
Cytokines
Gammaretrovirus
Gene therapy
Gene Transfer Techniques
General aspects
Genetic Diseases, X-Linked - genetics
Genetic Diseases, X-Linked - therapy
Genetic Therapy - adverse effects
Genetic Therapy - methods
Genetic Vectors
Histocompatibility antigen HLA
Humans
Humoral immunity
Immunity
Immunoglobulins
Immunoglobulins - blood
Immunology
Infant
Interleukin Receptor Common gamma Subunit
Leukemia
Lymphocyte Activation
Lymphocyte Culture Test, Mixed
Lymphocytes
Lymphocytes B
Lymphocytes T
Medical sciences
Morbidity
Mutation
Patients
Receptors, Interleukin-7 - genetics
Recovery of function
Restoration
Severe combined immunodeficiency
Severe Combined Immunodeficiency - genetics
Severe Combined Immunodeficiency - immunology
Severe Combined Immunodeficiency - therapy
Stem cells
T cell receptors
T-Lymphocytes - immunology
Transduction, Genetic
Transplantation
Transplants & implants
Viruses
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Description
Summary:X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor γchain(γc), 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. 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 γc vector and for functional immunological recovery. 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. Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(04)17590-9