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

J Allergy Clin Immunol. 2011 Jun;127(6):1376-84.e5. doi: 10.1016/j.jaci.2011.03.030. Epub 2011 Apr 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, T-Independent / administration & dosage
  • Autoantibodies / blood
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow Transplantation
  • Disease Models, Animal
  • Gene Expression
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Lentivirus / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • 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


  • Antigens, T-Independent
  • Autoantibodies
  • Recombinant Proteins
  • WAS protein, human
  • Was protein, mouse
  • Wiskott-Aldrich Syndrome Protein