title: Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Elena
authors.initials: E
authors.lastname: Draghici
authors.forename: Francesca
authors.initials: F
authors.lastname: Schena
authors.forename: Aisha Vanessa
authors.initials: AV
authors.lastname: Sauer
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.forename: Marco
authors.initials: M
authors.lastname: Catucci
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
mesh_terms: D000818:Animals; D000955:Antigens, T-Independent / Q000008:administration & dosage; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000955:Antigens, T-Independent; D001323:Autoantibodies; D011994:Recombinant Proteins; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein