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Gene therapy of severe combined immunodeficiencies

Abstract

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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Authors and Affiliations

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Correspondence to Alain Fischer.

Related links

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DATABASES

Entrez

GALV

HIV-1

Moloney murine sarcoma virus

LocusLink

ADA

Artemis

β2-integrin

CD3ɛ

CD3γ

CD24

CD34

CD45

DHFR

fibronectin

FLT3L

γc

GP91PHOX

IL-2

IL-3

IL-4

IL-7

IL-7Rα

IL-9

IL-11

IL-15

IL-21

IL-2 receptor α-chain

JAKs

JAK3

Jak3

MDR1

MGDF

NADPH oxidase

P22PHOX

P47PHOX

P67PHOX

RAG1

RAG2

SCF

STATs

WASP

ZAP70

OMIM

ADA deficiency

CGD

LAD

SCID-X

WAS

FURTHER INFORMATION

American Society of Gene Therapy

European Society for Immunodeficiencies

European Society of Gene Therapy

Glossary

BLOOD APHERESIS

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

CDR3-SEQUENCE DETERMINATION

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

COMMON LYMPHOID PROGENITOR

(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.

EX VIVO TRANSDUCTION

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

V(D)J RECOMBINATION

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). https://doi.org/10.1038/nri859

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