Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

TLDR

Wiskott‑Aldrich syndrome is an inherited immunodeficiency caused by mutations in WASP, and while hematopoietic stem‑cell transplants can be curative, autologous gene‑modified HSPCs offer an alternative when matched donors are unavailable. The study aimed to genetically correct HSPCs from three WAS patients using a lentiviral vector encoding functional WASP and reinfuse them after a reduced‑intensity conditioning regimen. The authors ex vivo transduced patient HSPCs with the lentiviral vector, then reinfused the corrected cells following conditioning. All three patients achieved stable engraftment of WASP‑expressing cells with improved platelet counts, immune function, and clinical scores, displayed highly polyclonal multilineage hematopoiesis, and showed no oncogene‑proximal integrations or clonal expansion over 20–32 months, indicating a promising but still unproven long‑term safety profile.

Abstract

Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.