B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome

Maria Carmina Castiello, Samantha Scaramuzza, Francesca Pala, Francesca Ferrua, Paolo Uva, Immacolata Brigida, Lucia Sereni, Mirjam Van Der Burg, Giorgio Ottaviano, Michael H. Albert, Maria Grazia Roncarolo, Luigi Naldini, Alessandro Aiuti, Anna Villa, Marita Bosticardo

Research output: Contribution to journalArticle


Background Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. Objective Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. Methods We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein. Results After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19+CD21-CD35- and CD21low B cells and a reduction in B cell-activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients. Conclusions We provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS.

Original languageEnglish
Pages (from-to)692-702.e2
JournalJournal of Allergy and Clinical Immunology
Issue number3
Publication statusPublished - Sep 1 2015


  • B cell
  • gene therapy
  • lentiviral vector
  • primary immunodeficiency
  • Wiskott-Aldrich syndrome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Castiello, M. C., Scaramuzza, S., Pala, F., Ferrua, F., Uva, P., Brigida, I., Sereni, L., Van Der Burg, M., Ottaviano, G., Albert, M. H., Grazia Roncarolo, M., Naldini, L., Aiuti, A., Villa, A., & Bosticardo, M. (2015). B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome. Journal of Allergy and Clinical Immunology, 136(3), 692-702.e2. https://doi.org/10.1016/j.jaci.2015.01.035