Hematopoietic Stem Cell Gene Therapy For Wiskott- Aldrich Syndrome

Wiskott Aldrich Syndrome (WAS) is a life-threatening primary immunodeficiency disorder characterized by susceptibility to infections, hemorrhage and malignancies. We here report the clinical, immunological, and molecular results of ten patients treated with transfusion of autologous genetically corrected hematopoietic stem cells between 2006 and 2009. After hematopoietic stem cell gene therapy with a gamma-retroviral vector, we observed phenotypical and functional reconstitution of lymphoid, myeloid cell lines and platelet numbers in 9/10 patients. Of note, patients had sustained correction of T-cell proliferation, immunological synapse formation and NK-cell mediated lysis, capacity to generate specific antibodies, and platelet production and size. All nine patients with sustained stem cell engraftment had marked clinical improvement with respect to infections, bleeding, and autoimmunity. Comprehensive analysis of retroviral insertions sites revealed a polyclonal hematopoiesis with more than 120.000 recurring loci. However, 5/10 of patients developed T-ALL (mean 1054.2d post GT; range 488-1813d post GT), each associated with a retroviral insertion in close proximity to the LMO2 locus. In 3/5 of patients with T-ALL (treatment according to AEIOP 2009 protocol) allogeneic HSCT due to poor initial response, minimal residual disease relapse, or cytological relapse was indicated. Further, one patient developed MDS like bone marrow changes and consecutively AML (1165d post GT), HSCT was performed in remission. Retrospectively, MDS1 clonal contribution to insertion sites showed a slow increase over the period of 22 month in this patient. GT has proven to revert the cellular and clinical phenotype of WAS but remains associated with considerable risk for insertional mutagenesis. Refining gene therapy strategies is an important goal for patients with WAS.