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In vivo correction of ZAP-70 immunodeficiency by intrathymic gene transfer
Oumeya Adjali, … , Naomi Taylor, David Klatzmann
Oumeya Adjali, … , Naomi Taylor, David Klatzmann
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2287-2295. https://doi.org/10.1172/JCI23966.
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Research Article Genetics

In vivo correction of ZAP-70 immunodeficiency by intrathymic gene transfer

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Abstract

SCID patients have been successfully treated by administration of ex vivo gene-corrected stem cells. However, despite its proven efficacy, such treatment carries specific risks and difficulties. We hypothesized that some of these drawbacks may be overcome by in situ gene correction of T lymphoid progenitors in the thymus. Indeed, in vivo intrathymic transfer of a gene that provides a selective advantage for transduced prothymocytes should result in the generation of functional T lymphocyte progeny, allowing long-term immune reconstitution. We assessed the feasibility of this approach in a murine model of ZAP-70–deficient SCID. A T cell–specific ZAP-70–expressing lentiviral vector was injected into thymi of adult ZAP-70–/– mice without prior conditioning. This resulted in the long-term differentiation of mature TCR-αβ+ thymocytes, indicating that the vector had integrated into progenitor cells. Moreover, peripheral ZAP-70–expressing T cells demonstrated a partially diversified receptor repertoire and were responsive to alloantigens in vitro and in vivo. Improved treatment efficacy was achieved in infant ZAP-70–/– mice, in which the thymus is proportionately larger and a higher percentage of prothymocytes are in cycle. Thus, intrathymic injection of a lentiviral vector could represent a simplified and potentially safer alternative to ex vivo gene-modified hematopoietic stem cell transplantation for gene therapy of T cell immunodeficiencies.

Authors

Oumeya Adjali, Gilles Marodon, Marcos Steinberg, Cédric Mongellaz, Véronique Thomas-Vaslin, Chantal Jacquet, Naomi Taylor, David Klatzmann

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Figure 1

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Schematic representation of the pCD4 lentiviral vector encoding WT ZAP-7...
Schematic representation of the pCD4 lentiviral vector encoding WT ZAP-70. The relative positions of the elements contained within the pCD4 lentiviral vector are indicated. Both 3′ and 5′ long terminal repeats (LTRs) are derived from Rous Sarcoma Virus (RSV). SD, splice donor; SA, splice acceptor; Ψ, packaging signal; ga-RRE, truncated gag sequence with the rev responsive element; cPPT, central polypurine tract of HIV; CD4pmE, human CD4 minimal promoter/murine enhancer cassette (590 bp); ZAP-70, ZAP-70 cDNA; eGFP, eGFP cDNA; WPRE, posttranscriptional cis-acting regulatory element of the woodchuck hepatitis virus (587 bp); LTR-SIN, self-inactivating 3′-LTR deleted of 400 bp in the U3 region (29); U3, untranslated 3′ region of the LTR; and R, repeated region of the LTR.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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