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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 2

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Thymocyte differentiation in ZAP-70–/– mice following in situ injection ...
Thymocyte differentiation in ZAP-70–/– mice following in situ injection of pT-ZAP. pT-ZAP was injected IT into 8- to 12-week-old ZAP-70–/– mice, and thymocytes were harvested from euthanized animals 7–13 weeks later. (A) Total thymocytes were stained with Cy-conjugated α-CD8 and APC-conjugated α-CD4mAbs. The percentages of DP and CD4+ and CD8+ SP thymocytes in WT (C57BL/6), ZAP-70–/–, and in mice reconstituted in vivo are indicated in each dot plot. (B) The percentages of eGFP+ cells within the entire thymus as well as within the thymocyte subset wherein TCRβ was upregulated are shown. The CD4/CD8 distributions of TCR-β–upregulated thymocytes within the eGFP– population of ZAP-70–/– and WT mice are shown. Additionally, the CD4/CD8 distributions within the eGFP– and eGFP+ TCR-β–upregulated populations in ZAP-70–/– mice injected with pT-ZAP are compared. The mouse injected IT was sacrificed at 8 weeks after treatment. Results are representative of data obtained from 6 mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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