Preclinical Safety and Efficacy of human CD34 + Cells transduced with lentiviral vector for the treatment of wiskott-aldrich syndrome

Samantha Scaramuzza, Luca Biasco, Anna Ripamonti, Maria C. Castiello, Mariana Loperfido, Elena Draghici, Raisa J. Hernandez, Fabrizio Benedicenti, Marina Radrizzani, Monica Salomoni, Marco Ranzani, Cynthia C. Bartholomae, Elisa Vicenzi, Andrea Finocchi, Robbert Bredius, Marita Bosticardo, Manfred Schmidt, Christof Von Kalle, Eugenio Montini, Alessandra BiffiMaria G. Roncarolo, Luigi Naldini, Anna Villa, Alessandro Aiuti

Research output: Contribution to journalArticle

Abstract

Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34 + cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34 + cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34 + cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34 + cells gene therapy for the treatment of WAS.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalMolecular Therapy
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 2013

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ASJC Scopus subject areas

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

Cite this

Scaramuzza, S., Biasco, L., Ripamonti, A., Castiello, M. C., Loperfido, M., Draghici, E., Hernandez, R. J., Benedicenti, F., Radrizzani, M., Salomoni, M., Ranzani, M., Bartholomae, C. C., Vicenzi, E., Finocchi, A., Bredius, R., Bosticardo, M., Schmidt, M., Von Kalle, C., Montini, E., ... Aiuti, A. (2013). Preclinical Safety and Efficacy of human CD34 + Cells transduced with lentiviral vector for the treatment of wiskott-aldrich syndrome. Molecular Therapy, 21(1), 175-184. https://doi.org/10.1038/mt.2012.23