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Gene therapy of severe combined immunodeficiencies


The concept that the outcome of a devastating disease can be modified by inserting a transgene into abnormal cells is appealing. However, the gene-transfer technologies that are available at present have limited the success of gene therapy so far. Nevertheless, severe combined immunodeficiencies are a useful model, because gene transfer can confer a selective advantage to transduced cells. In this way, a proof of concept for gene therapy has been provided.

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Figure 1: Defects in T-cell development that result in severe combined immunodeficiencies.
Figure 2: Schemes of γ-chain-containing cytokine receptors.
Figure 3: Principle of ex vivo gene therapy of the SCID-X condition.
Figure 4: Scheme of the transduction protocol for the SCID-X gene-therapy trial.

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Correspondence to Alain Fischer.

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Moloney murine sarcoma virus
























IL-2 receptor α-chain






NADPH oxidase











ADA deficiency






American Society of Gene Therapy

European Society for Immunodeficiencies

European Society of Gene Therapy



The ex vivo selection of blood cells. Unwanted cells are infused back into the donor.


Sequencing of the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor genes of individual T-cell clones.


(CLP). A progenitor that is committed to the lymphoid lineage that can give rise to all lymphocyte subsets, including T cells, B cells and natural killer cells.


The ex vivo insertion of a transgene into cells. Cells are then placed back into the host.


Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of antigen-receptor-encoding genes, which leads to the repertoire diversity of both T- and B-cell receptors.

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Fischer, A., Hacein-Bey, S. & Cavazzana-Calvo, M. Gene therapy of severe combined immunodeficiencies. Nat Rev Immunol 2, 615–621 (2002).

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