Int J Hematol 2025 Nov 12; doi: 10.1007/s12185-025-04099-6.

Advancements in gene therapy for Wiskott-Aldrich syndrome: from early trials to emerging approaches.

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by microthrombocytopenia, eczema, recurrent infections, and immune dysregulation, affecting approximately 1 in 100,000 live births. While the disorder was historically fatal in early childhood, advances in hematopoietic stem cell transplantation (HSCT), gene therapy, and supportive care have improved survival, though morbidity remains high. Mutations in the WAS gene disrupt the WAS protein (WASp), which is essential for actin cytoskeleton dynamics, thereby impairing immune cell function. Over 466 mutations correlate with disease severity, from severe classic WAS to milder X-linked thrombocytopenia (XLT). Supportive therapies manage symptoms, while HSCT offers a cure for severe cases. Gene therapy has emerged as a promising alternative, with early gamma-retroviral trials showing efficacy but also a risk of leukemogenesis. Third-generation lentiviral vectors with self-inactivating LTRs (long terminal repeats) demonstrate improved safety and immune restoration in clinical trials. This review evaluates the evolution of gene therapy for WAS, from early trials to emerging genome editing approaches, assessing their efficacy, safety, and potential to transform clinical outcomes.

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