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Preclinical Safety and Efficacy of Human CD34(+) Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome
Preclinical Safety and Efficacy of Human CD34(+) Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome MOLECULAR THERAPY 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., Biffi, A., Roncarolo, M. G., Naldini, L., Villa, A., Aiuti, A. 2013; 21 (1): 175-184Abstract
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.
View details for DOI 10.1038/mt.2012.23
View details for Web of Science ID 000313035000020
View details for PubMedID 22371846