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

The goal of this study was to develop a clinical protocol for Wiskott-Aldrich syndrome (WAS) by using a lentiviral vector (LV) to introduce a functional WAS gene into hematopoietic stem and progenitor cells (HSPCs) for autologous transplantation.Three patients who had WAS with a severe clinical condition or severe mutation/absent WAS protein expression without a suitable matched donor for allogeneic transplant or ineligible for HSPC transplantation were enrolled.Patients were pretreated with a reduced-intensity myeloablative regimen. Afterward, they received autologous HSPCs that were transduced with an optimized LV carrying the WAS gene. Patients were monitored for up to 2.5 years after gene therapy, and the genomic distribution of LV integration sites in bone marrow and peripheral blood lineages was investigated.Researchers were able to administer autologous HSPCs transduced with LV with high efficiency (>90%). This technique resulted in robust (25%–50%) and long-term engraftment in bone marrow, as well as detection of WAS protein expression in peripheral blood. All 3 patients experienced improved platelet counts, protection from bleeding and severe infections, and resolution of eczema. Analysis of LV integration resulted in highly polyclonal multilineage hematopoietic reconstitution with no in vivo selection of clones carrying integrations near oncogenes, as had been seen with previous γ-retroviral gene therapy.The authors concluded that gene therapy using lentiviral HSPCs results in hematopoietic reconstitution and restoration of WAS expression to near physiologic levels in patients with resultant clinical benefit. There was no increased risk of malignant transformation as seen with γ-retroviral gene therapy in the same disease setting.Infusion of autologous HSPCs that have been genetically corrected ex vivo is an alternative therapeutic strategy for patients with WAS for whom a fully matched allogeneic donor is unavailable. Previous gene therapy in WAS patients using the γ-retroviral vector showed initial clinical benefit but was later associated with development of leukemia or myelodysplasia. This study addresses a potentially safer alternative with the use of the LV carrying the WAS gene under the control of its endogenous promoter to ensure that the transgene is expressed in a physiologic manner. Because there is currently no curative treatment of WAS other than a fully matched allogeneic HSPC transplant, LV gene therapy could be an attractive treatment option for patients. It would be of particular interest because of its safety profile compared with previous therapies because WAS patients are already innately prone to developing malignancies. Future studies with the use of a larger patient population will likely provide information about indications for LV gene therapy as an alternative to traditional stem cell transplantation.