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Gene therapy for Wiskott–Aldrich syndrome

Introduction: Wiskott–Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the WAS gene. The phenotype comprises thrombocytopenia, immunodeficiency, autoimmunity and predisposition to malignancy. Untreated, classical WAS is lethal within the first two decades of life. Until recently, the only curative therapy was allogeneic hematopoietic stem cell transplantation. This procedure is associated with considerable risks, in particular, if no matched stem cell donors are available. Areas covered: Feasibility, efficacy and sustainability of gene therapy (GT) for WAS and other primary immunodeficiencies (PIDs) have been shown. However, retroviral GT is still associated with considerable risk for insertional mutagenesis (IM) leading to hematological malignancy. Investigation of mutagenesis and its relation to vector design, the underlying disease, milieu factors and target cell characteristics is needed and will be discussed. Lentiviral self-inactivating (SIN) vectors with potentially improved toxicity profiles have been developed, but long-term efficacy is unknown. Ultimately, correction of defined mutations by designer nucleases might become clinically available. Expert opinion: Despite long-term clinical benefits, uncontrolled clonal expansion remains a critical limitation. Risks and benefits of GT and allogeneic hematopoietic stem cell transplantation must be weighted considering remission, safety profiles, side effects, availability and cost effectiveness.