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Lymphopoiesis in transgenic mice over-expressing Artemis

Gene Therapy volume 23, pages 176–186 (2016)Cite this article

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Abstract

Artemis is a factor of the non-homologous end joining pathway involved in DNA double-strand break repair that has a critical role in V(D)J recombination. Mutations in DCLRE1C/ARTEMIS gene result in radiosensitive severe combined immunodeficiency in humans owing to a lack of mature T and B cells. Given the known drawbacks of allogeneic hematopoietic stem cell transplantation (HSCT), gene therapy appears as a promising alternative for these patients. However, the safety of an unregulated expression of Artemis has to be established. We developed a transgenic mouse model expressing human Artemis under the control of the strong CMV early enhancer/chicken beta actin promoter through knock-in at the ROSA26 locus to analyze this issue. Transgenic mice present a normal development, maturation and function of T and B cells with no signs of lymphopoietic malignancies for up to 15 months. These results suggest that the over-expression of Artemis in mice (up to 40 times) has no deleterious effects in early and mature lymphoid cells and support the safety of gene therapy as a possible curative treatment for Artemis-deficient patients.

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Acknowledgements

We thank Dr P Revy, Dr D Moshous, Dr I André-Schmutz and Dr C Lagresle-Peyrou for helpful discussion during the project. This work was supported by institutional grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Ligue Nationale contre le Cancer (Equipe labellisée LA LIGUE), the Institut National du Cancer (INCa/IdF) and the European Research Council (ERC) (249816 PIDIMMUN). PR-M was supported by the Agence Nationale de la Recherche.

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Authors and Affiliations

  1. Laboratory of Genome Dynamics in the Immune System (DGSI), INSERM UMR1163, Paris, France

    P Rivera-Munoz, V Abramowski & J-P de Villartay

  2. Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France

    P Rivera-Munoz, V Abramowski, A Fischer, M Cavazzana & J-P de Villartay

  3. Institut Clinique de la Souris, PHENOMIN, CNRS, INSERM, Université de Strasbourg, Illkirch, France

    S Jacquot & P André

  4. Généthon, Evry, France

    S Charrier & A Galy

  5. Service des Animaux Transgéaniques, UPS44, CNRS, Villejuif, France

    K Lipson-Ruffert

  6. Unité d’Immunologie et Hématologie Pédiatrique, AP/HP, Hôpital Necker-Enfants Malades, Paris, France

    A Fischer & M Cavazzana

  7. Collège de France, Paris, France

    A Fischer

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  1. P Rivera-Munoz
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Correspondence to J-P de Villartay.

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Rivera-Munoz, P., Abramowski, V., Jacquot, S. et al. Lymphopoiesis in transgenic mice over-expressing Artemis. Gene Ther 23, 176–186 (2016). https://doi.org/10.1038/gt.2015.95

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