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

Fatine Benjelloun 1 Alexandrine Garrigue 1 Corinne Demerens-de Chappedelaine 1 Pauline Soulas-Sprauel 1 Michele Malassis-Séris 1 Daniel Stockholm 2 Julia Hauer 1 Johanna Blondeau 2 Julie Rivière 1 Annick Lim 3 Marc Le Lorc'H 4 Serge Romana 4 Nicole Brousse 5 Frederique Pâques 6 Anne Galy 2 Pierre Charneau 7 Alain Fischer 1, 8 Jean-Pierre de Villartay 1, 9 Marina Cavazzana-Calvo 1, 10, *
* Corresponding author
1 Developpement Normal et Pathologique du Système Immunitaire
2 Généthon
3 Développement des Lymphocytes
4 Service d'Histologie-Embryologie et Cytogénétique Assistance Publique
5 Service d'Anatomie et Cytologie Pathologique
6 Cellectis SA
7 Virologie moléculaire et Vectorologie
8 Unité d'Immunologie et Hématologie Pédiatrique
9 Service d'Hématologie
10 Département de Biothérapie [CHU Necker]
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 Connect in order to contact the contributor
Submitted on : Thursday, February 18, 2010 - 2:24:41 PM
Last modification on : Wednesday, October 27, 2021 - 3:00:19 PM

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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, Cell Press, 2008, 16 (8), pp.1490-9. ⟨10.1038/mt.2008.118⟩. ⟨pasteur-00457775⟩

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