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

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• 作者：Maria Carmina Castiello ; PhD^a ; Samantha Scaramuzza ; PhD^a ; Francesca Pala ; MS^a ; Francesca Ferrua ; MD^b ; Paolo Uva ; PhD^c ; Immacolata Brigida ; PhD^a ; Lucia Sereni ; MS^a ; Mirjam van der Burg ; PhD^d ; Giorgio Ottaviano ; MD^b ; Michael H. Albert ; MD^e ; Maria Grazia Roncarolo ; MD^a ; ^f ; Luigi Naldini ; MD ; PhD^a ; ^f ; Alessandro Aiuti ; MD ; PhD^a ; ^g ; Anna Villa ; MD^a ; ^h ; ^{villa.anna@hsr.it" class="auth_mail" title="E-mail the corresponding author} ; Marita Bosticardo ; PhD^a
• 关键词：Wiskott-Aldrich syndrome ; gene therapy ; B cell ; primary immunodeficiency ; lentiviral vector
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：136
• 期：3
• 页码：692-702.e2
• 全文大小：2445 K

文摘

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 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.