Authors:
Christian Jörg Braun, Kaan Boztug, Anna Paruzynski, Maximilian Witzel, Adrian Schwarzer, Michael Rothe, Ute Modlich, Rita Beier, Gudrun Göhring, Doris Steinemann, Raffaele Fronza, Claudia Regina Ball, Reinhard Haemmerle, Sonja Naundorf, Klaus Kühlcke, Martina Rose, Chris Fraser, Liesl Mathias, Rudolf Ferrari, Miguel R. Abboud, Waleed Al-Herz, Irina Kondratenko, László Maródi, Hanno Glimm, Brigitte Schlegelberger, Axel Schambach, Michael Heinrich Albert, Manfred Schmidt, Christof von Kalle, and Christoph Klein
Summary:
Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
Source:
Science Translational Medicine; Vol. 6, Issue 227, 227ra33 (03/12/14)