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Abstract
Wiskott–Aldrich syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott–Aldrich syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.
Financial & competing interests disclosure
AJ Thrasher is supported by grants from the Wellcome Trust, the Great Ormond Street Hospital Biomedical Research Centre and the Great Ormond Street Hospital Children’s Charity and the European Union Seventh Framework Program for Research (CELL-PID 261387). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Wiskott–Aldrich Syndrome (WAS) is caused by mutations in the actin nucleation-promoting factor WASp, resulting is disruption of wide range of immune cellular functions, including phagocytosis, cytotoxic granule release, cell polarization, chemotaxis, regulation of cell shape and antigen receptor signaling. Recent advances also suggest a role in transcriptional reprogramming of T cells in an actin-independent function.
Early onset of autoimmunity, severe refractory thrombocytopenia and the development of malignancy suggest the most severe clinical phenotype in WAS, and these patients need urgent curative treatment (stem cell transplant or gene therapy), prior to the development of life-threatening complications.
Although the phenotype–proteotype–genotype correlation in WAS is not absolute, a combination of this information can be used to predict which patients will most benefit from pre-emptive stem cell transplantation. Deletion, nonsense and complex mutations causing an absence of WASp expression tend to be associated with more severe clinical phenotype, and missense mutations associated with residual WASp expression tend to cause X-linked thrombocytopenia.
Supportive care in WAS should include antimicrobial prophylaxis, immunoglobulin replacement therapy, feeding with a hypoallergenic milk, topical steroids and antimicrobials for eczema, and aggressive, early treatment of autoimmune complications. Rituximab in combination with corticosteroids is useful in treating autoimmune cytopenias.
Outcomes from hematopoietic stem cell transplantation in WAS have significantly improved over the past 20 years, and current data suggest overall survival rates of greater than 90%. Early transplantation prior to the development of clinical complications is associated with the best outcomes, and the optimal age of transplant is 1–2 years of age.
Mixed donor chimerism causing thrombocytopenia and autoimmunity post HSCT are common and significant complications. Autoimmunity can be treatment refractory and long lived, whereas thrombocytopenia can be improved by splenectomy, resulting in significantly improved quality of life in selected patients.
Gene therapy trials have demonstrated that WAS can be cured by viral vector gene correction of autologous stem cells, and nonmyeloablative conditioning. Recent self-inactivating lentiviral vector trials have demonstrated clinical benefit with no evidence of vector integration driven oncogenesis or clonal expansion. This approach offers a low toxicity treatment for patients without a full HLA-matched donor.