Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome

Sum m a r yThe Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity.We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC).We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy.T and B cells, natural killer (NK) cells, and monocytes were functionally corrected.After treatment, the patients’ clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection.Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis.(Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.)T he Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder that is characterized by recurrent infections, thrombocytopenia, eczema, and autoimmunity 1,2 and caused by mutations in WAS. 3 Its gene product, WAS protein (WASP), is a key regulator of actin polymerization in he ma topoietic cells, with domains involved in signaling, cell locomotion, and immunologic-synapse formation.4 The complex biologic features of this disease result from multiple dysfunctions in different subgroups of leukocytes, including defective function of T and B cells, disturbed formation of the NK-cell immunologic synapse, and impaired migratory responses in all leukocyte subgroups.4,5 Severe WAS leads to an early death from infection or bleeding.6 Currently, the only curative therapy consists of allogeneic HSC transplantation, which may be associated with considerable risk of death or complications related to transplantation.7 HSC gene therapy has emerged as an innovative therapeutic strategy for various primary immunodeficiency disorders.8-12 WAS is a promising candidate disease for gene-therapy approaches, since WASP expression is restricted to cells of the hematopoietic system, which grants a proliferative advantage over WASP-negative cells.13,14 Preclinical studies have shown efficient reconstitution of cellular function in vitro and in vivo.13 On the basis of our own preclinical in vitro and in vivo studies, 15,16 we developed a clinical gene-transfer protocol.13 Here we report the results in two young boys who were treated with HSC gene therapy.