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Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells.

Abstract : Patients with mutations in the Artemis gene display a complete absence of T- and B lymphocytes, together with increased cellular radiosensitivity; this leads to a radiosensitive severe combined immunodeficiency (RS-SCID). Allogenic hematopoietic stem-cell (HSC) transplantation is only partially successful in the absence of an human leukocyte antigen-genoidentical donor, and this has prompted a search for alternative therapeutic approaches such as gene therapy. In this study, a self-inactivated lentiviral vector expressing Artemis was used to complement the Artemis knockout mouse (Art(-/-)). Transplantation of Artemis-transduced HSCs into irradiated Art(-/-) mice restored a stable (over a 15-month period of follow-up) and functional T- and cell repertoire that was comparable to that of control mice. The success of secondary transplantations demonstrated that the HSCs had been transduced. One of thirteen mice developed a thymoma 6 months after gene therapy. Although thymic cells were seen to be carrying two lentiviral integration sites, there was no evidence of lentivirus-driven oncogene activation. The Art(-/-) mice were found to be prone to develop T-cell lymphomas, either spontaneously or after irradiation. These data indicate that the observed lymphoproliferation was probably the consequence of the chromosomal instability associated with the Artemis-deficient background. As a whole, our work provides a basis for supporting the gene therapy approach in Artemis-deficient SCID.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00457775
Contributor : Mireille Gau <>
Submitted on : Thursday, February 18, 2010 - 2:24:41 PM
Last modification on : Wednesday, August 19, 2020 - 11:16:55 AM

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Fatine Benjelloun, Alexandrine Garrigue, Corinne Demerens-de Chappedelaine, Pauline Soulas-Sprauel, Michele Malassis-Séris, et al.. Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells.. Molecular Therapy, Nature Publishing Group, 2008, 16 (8), pp.1490-9. ⟨10.1038/mt.2008.118⟩. ⟨pasteur-00457775⟩

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