| Summary: | Kanwaldeep K Mallhi,1– 3 Aleksandra Petrovic,1,2,4,* Hans D Ochs2,5,* 1Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; 3Division of Hematology and Oncology, Seattle Children’s Hospital, Seattle, WA, USA; 4Division of Immunology and Division of Hematology and Oncology, Seattle Children’s Hospital, Seattle, WA, USA; 5Seattle Children’s Research Institute, Seattle, WA, USA*These authors contributed equally to this workCorrespondence: Hans D OchsDepartment of Pediatrics, University of Washington School of Medicine, Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA, 98101-1304, USAEmail allgau@uw.eduAbstract: The Wiskott–Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the WAS gene resulting in congenital thrombocytopenia, eczema, recurrent infections and an increased incidence of autoimmune diseases and malignancies. Without curative therapies, affected patients have diminished life expectancy and reduced quality of life. Since WAS protein (WASP) is constitutively expressed only in hematopoietic stem cell-derived lineages, hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are well suited to correct the hematologic and immunologic defects. Advances in high-resolution HLA typing, new techniques to prevent GvHD allowing the use of haploidentical donors, and the introduction of reduced intensity conditioning regimens with myeloablative features have increased overall survival (OS) to over 90%. The development of GT for WAS has provided basic knowledge into vector selection and random integration of various viral vectors into the genome, with the possibility of inducing leukemogenesis. After trials and errors, inactivating lentiviral vectors carrying the WAS gene were successfully evaluated in clinical trials, demonstrating cure of the disease except for insufficient resolution of the platelet defect. Thus, 50 years of clinical evaluation, genetic exploration and extensive clinical trials, a lethal syndrome has turned into a curable disorder.Keywords: Wiskott–Aldrich syndrome, WAS, X-linked thrombocytopenia, XLT, X-linked neutropenia, XLN, hematopoietic stem cell transplantation, HSCT, reduced intensity conditioning, gene therapy, GT, lentiviral vectors
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