Gene therapy for Wiskott–Aldrich syndrome

Abstract

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.

Keywords::

• immunodeficiency
• stem cell gene therapy
• Wiskott–Aldrich syndrome

Acknowledgment

We thank our clinical and scientific collaborators from the Dr von Hauner Children's Hospital, Ludwig-Maximilian University Munich; from Hannover Medical School, Hannover; from the National Tumor Center, Heidelberg; from the University of Heidelberg, Medical School, Heidelberg; the EUFETS GmbH, Idar-Oberstein; as well as our clinical national and international collaborators.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Notes

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