B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome - 04/09/15
, Marita Bosticardo, PhD aAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Wiskott-Aldrich syndrome, gene therapy, B cell, primary immunodeficiency, lentiviral vector
Abbreviations used : BAFF, BM, GT, HD, HSC, IVIg, PB, SDF-1α, VCN, WAS, WASp
Plan
| Supported by Telethon (TIGET Core grant A2 to A.V.), Ministero della Salute (RF 2009 Giovani Ricercatori Grant, to M.v.d.B.), EU project CELL PID (FP7 no. 261387 to A.A. and A.V.). M.v.d.B. is supported by the Dutch Scientific organization (ZonMW Vidi grant no. 016.126.323). L.S. conducted this study as partial fulfillment of her PhD in Molecular Medicine, Program in Basic and Applied Immunology, San Raffaele University, Milan, Italy. Since January 2014, GlaxoSmithKline has in-licensed the WAS gene therapy program and has become the financial sponsor of the clinical trial conducted at TIGET. |
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| Disclosure of potential conflict of interest: This work was supported by Telethon (TIGET Core grant A2 to A.V.), Ministero della Salute (RF 2009 Giovani Ricercatori Grant), and EU project CELL PID (FP7 no. 261387). L. Sereni conducted this study as partial fulfillment of her PhD in Molecular Medicine, Program in Basic and Applied Immunology, San Raffaele University, Milan, Italy. M. van der Burg is supported by Dutch Scientific organization (ZonMW Vidi grant 016.126.323). Since January 2014, GlaxoSmithKline has in-licensed the WAS gene therapy program and has become the financial sponsor of the clinical trial conducted at TIGET. M. H. Albert has received stock options from Amgen and JUNO Pharmaceuticals. The authors declare that they have no other relevant conflicts of interest. |
Vol 136 - N° 3
P. 692 - septembre 2015 Retour au numéro
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