Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models

Francesco Marangoni, Marita Bosticardo, Sabine Charrier, Elena Draghici, Michela Locci, Samantha Scaramuzza, Cristina Panaroni, Maurilio Ponzoni, Francesca Sanvito, Claudio Doglioni, Marie Liabeuf, Bernard Gjata, Marie Montus, Katherine Siminovitch, Alessandro Aiuti, Luigi Naldini, Loïc Dupré, Maria Grazia Roncarolo, Anne Galy, Anna Villa

Research output: Contribution to journalArticle

Abstract

Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of wasnull mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.

Original languageEnglish
Pages (from-to)1073-1082
Number of pages10
JournalMolecular Therapy
Volume17
Issue number6
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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    Marangoni, F., Bosticardo, M., Charrier, S., Draghici, E., Locci, M., Scaramuzza, S., Panaroni, C., Ponzoni, M., Sanvito, F., Doglioni, C., Liabeuf, M., Gjata, B., Montus, M., Siminovitch, K., Aiuti, A., Naldini, L., Dupré, L., Roncarolo, M. G., Galy, A., & Villa, A. (2009). Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models. Molecular Therapy, 17(6), 1073-1082. https://doi.org/10.1038/mt.2009.31