From oncogenesis to approval: the lentiviral gene therapy revolution in Wiskott-Aldrich syndrome.

Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by pathogenic variants in the WAS gene, resulting in absent or dysfunctional WAS protein (WASp) and a clinical triad of eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation has historically represented the only curative option, but outcomes are constrained by donor availability, graft-versus-host disease, and transplant-related toxicity. Autologous gene therapy emerged as a compelling alternative. Early gammaretroviral vector trials confirmed that <i>ex vivo</i> correction of hematopoietic stem and progenitor cells could restore WASp expression and produce meaningful clinical benefit. However, insertional oncogenesis exposed an unacceptable genotoxic liability and drove the field toward self-inactivating lentiviral vectors. Clinical trials employing lentiviral platforms demonstrated durable, multi-lineage engraftment, sustained WASp expression, and robust immune reconstitution, with no reported cases of vector-related leukemia. These outcomes culminated in the FDA approval of WASKYRA (etuvetidigene autotemcel) in December 2025, establishing autologous gene therapy as a licensed standard of care for WAS patients lacking a suitable HLA-matched related donor. Next-generation precision gene-editing strategies and <i>in vivo</i> delivery platforms offer a path toward safer and more accessible correction. This review traces the full arc of WAS gene therapy, from early preclinical proof of concept through regulatory approval. Wiskott-Aldrich syndrome (WAS) is a rare genetic disorder that primarily affects boys. Caused by an inherited gene mutation, it compromises the immune system, triggers severe eczema, and causes dangerous bleeding and bruising due to low platelet levels. Patients also face an elevated risk of autoimmune diseases and cancer, and without intervention, the condition is typically fatal before adulthood.Historically, the only curative option was a bone marrow transplant from a matched donor, a procedure fraught with risks and limited by donor availability. Gene therapy has emerged as a highly promising alternative. By extracting a patient&#x2019;s own blood-forming stem cells and using a modified virus to deliver a healthy copy of the WAS gene, doctors can restore function without the risk of immune rejection. While early iterations of this therapy triggered leukemia in some children, advancements in viral delivery systems have led to a much safer approach. This updated method has now been successfully administered to dozens of patients globally, yielding positive long-term outcomes with no reported cases of leukemia.This article provides a comprehensive review of WAS gene therapy&#x2019;s evolution, highlighting the results of major clinical trials to date. Finally, it explores future innovations, such as advanced precision gene-editing technologies, and discusses strategies to make these life-saving treatments more affordable and accessible on a global scale.