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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:136

Article

Castiello, Maria Carmina¹  Scaramuzza, Samantha¹  Pala, Francesca¹  Ferrua, Francesca²  Uva, Paolo³  Brigida, Immacolata¹  Sereni, Lucia¹  van der Burg, Mirjam⁴  Ottaviano, Giorgio²  Albert, Michael H.⁵  Roncarolo, Maria Grazia^1,6  Naldini, Luigi^1,6  Aiuti, Alessandro^1,7  Villa, Anna^1,8  Bosticardo, Marita¹ 

[1] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy TIGET, I-20132 Milan, Italy

[2] IRCCS San Raffaele Sci Inst, Pediat Immunohematol & Bone Marrow Transplantat U, I-20132 Milan, Italy

[3] Sci & Technol Pk Polaris, CRS4, Cagliari, Italy

[4] Univ Med Ctr, Erasmus MC, Dept Immunol, Rotterdam, Netherlands

[5] Univ Munich, Dr von Hauner Childrens Hosp, Munich, Germany

[6] Univ Vita Salute San Raffaele, Milan, Italy

[7] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy

[8] IRGB CNR, Milan Unit, Milan, Italy

关键词: Wiskott-Aldrich syndrome;    gene therapy;    B cell;    primary immunodeficiency;    lentiviral vector;   

DOI  :  10.1016/j.jaci.2015.01.035

来源: Elsevier

【 摘 要 】

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 transducedBcells 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 CD21(low) 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.

【 授权许可】

Free