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A lentiviral vector encoding the human Wiskott–Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice

Gene Therapy volume 12, pages 597–606 (2005)Cite this article

Abstract

Wiskott–Aldrich syndrome (WAS) is an immune deficiency with thrombopenia resulting from mutations in the WASP gene. This gene normally encodes the Wiskott–Aldrich syndrome protein (WASP), a major cytoskeletal regulator expressed in hematopoietic cells. Gene therapy is a promising option for the treatment of WAS, requiring that clinically applicable WASP gene transfer vectors demonstrate efficacy in preclinical studies. Here, we describe a self-inactivating HIV-1-derived lentiviral vector encoding human WASP and show that it effectively transduced bone marrow progenitor cells of WASP knockout (WKO) mice. Transplantation of these transduced cells into lethally irradiated WKO recipients led to stable expression of WASP and correction of immune, inflammatory and cytoskeletal defects. Splenic T-cell proliferation was restored, podosomes were reinstated on bone-marrow-derived dendritic cells and colon inflammation was reduced. This shows for the first time (a) that cytoskeletal defects can be corrected in WKO mice, (b) that human WASP is biologically active in mice and (c) that a lentiviral vector is effective to express human WASP in vivo over several months. These data support further development of such lentiviral vectors for the gene therapy of WAS.

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Acknowledgements

We are grateful to Dr S Snapper, Harvard Medical School for the gift of WKO mice. We are thankful to our colleagues at Genethon, G Griffith for vector construction, B Gjata and I Adamski for help with histology and to Dr J Davoust for help with confocal microscopy. We would also like to acknowledge the dedicated care provided to the mice by the personnel of the Institut Gustave Roussy animal facility. This study was supported in part by equipment funds from ‘Génopole Recherche’, Evry, France and from the ‘Fondation pour la Recherche Médicale’, Paris, France.

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Authors and Affiliations

  1. Genethon UMR CNRS 8115, Evry, France

    S Charrier, D Stockholm, K Seye, M Taveau, D-A Gross, S Bucher-Laurent, C Delenda, O Danos & A Galy

  2. UMR 8121, Institut Gustave Roussy, Villejuif, France

    P Opolon

  3. INSERM U362, Institut Gustave Roussy, Villejuif, France

    W Vainchenker & A Galy

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  1. S Charrier
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Charrier, S., Stockholm, D., Seye, K. et al. A lentiviral vector encoding the human Wiskott–Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice. Gene Ther 12, 597–606 (2005). https://doi.org/10.1038/sj.gt.3302440

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