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

• Published in: Journal of allergy and clinical immunology 2011-06, Vol.127 (6), p.1376-1384.e5
• Main Authors: Bosticardo, Marita, PhD, Draghici, Elena, MS, Schena, Francesca, PhD, Sauer, Aisha Vanessa, PhD, Fontana, Elena, PhD, Castiello, Maria Carmina, MS, Catucci, Marco, PhD, Locci, Michela, PhD, Naldini, Luigi, MD, PhD, Aiuti, Alessandro, MD, PhD, Roncarolo, Maria Grazia, MD, Poliani, Pietro Luigi, MD, PhD, Traggiai, Elisabetta, PhD, Villa, Anna, MD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Antigens, T-Independent - administration & dosage; Autoantibodies - blood; autoimmunity; B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biological and medical sciences; Bone marrow; Bone Marrow Transplantation; Cloning; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Hematologic and hematopoietic diseases; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Laboratories; lentiviral vectors; Lentivirus - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet diseases and coagulopathies; primary immunodeficiency; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Spleen; Stem cells; Streptococcus pneumoniae; Transplants & implants; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - immunology; Wiskott-Aldrich Syndrome - therapy; Wiskott-Aldrich Syndrome Protein - deficiency; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - metabolism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.03.030

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.