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 ex vivo 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 in vivo 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.