Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome

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• 作者：Marita Bosticardo PhD^a ; Elena Draghici MS^a ; Francesca Schena PhD^b ; Aisha Vanessa Sauer PhD^a ; Elena Fontana PhD^c ; Maria Carmina Castiello MS^a ; Marco Catucci PhD^a ; Michela Locci PhD^a ; Luigi Naldini MD ; PhD^a ; ^d ; Alessandro Aiuti MD ; PhD^a ; ^e ; Maria Grazia Roncarolo MD^a ; ^d ; Pietro Luigi Poliani MD ; PhD^c ; Elisabetta Traggiai PhD^b ; Anna Villa MD^a ; ^f ; ^{anna.villa@itb.cnr.it"" rel=""nofollow} ; ^{villa.anna@hsr.it"" rel=""nofollow}
• 关键词：Gene therapy ; lentiviral vectors ; primary immunodeficiency ; Wiskott-Aldrich syndrome ; B cells ; autoimmunity
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：127
• 期：6
• 页码：1376-1384.e5
• 全文大小：2171 K

文摘

Background

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, eczema, infections, autoimmunity, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical donors is curative, but it is not available to all patients. We have developed a gene therapy (GT) approach for WAS by using a lentiviral vector encoding for human WAS promoter/cDNA (w1.6W) and demonstrated its preclinical efficacy and safety.

Objective

To evaluate B-cell reconstitution and correction of B-cell phenotype in GT-treated mice.

Methods

We transplanted Was^−/− mice sublethally irradiated (700 rads) with lineage marker-depleted bone marrow wild-type cells, Was^−/− cells untransduced or transduced with the w1.6W lentiviral vector and analyzed B-cell reconstitution in bone marrow, spleen, and peritoneum.

Results

Here we show that WAS protein⁺ B cells were present in central and peripheral B-cell compartments from GT-treated mice and displayed the strongest selective advantage in the splenic marginal zone and peritoneal B1 cell subsets. After GT, splenic architecture was improved and B-cell functions were restored, as demonstrated by the improved antibody response to pneumococcal antigens and the reduction of serum IgG autoantibodies.

Conclusion

WAS GT leads to improvement of B-cell functions, even in the presence of a mixed chimerism, further validating the clinical application of the w1.6W lentiviral vector.