Outcomes of Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplant for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase I/II clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral (SIN-LV) vector expressing the human WAS cDNA under the control of a 1.6kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All subjects were alive and well with sustained multi-lineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections and bleeding diathesis was universal. Immune function was consistently improved despite sub-physiological levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity post-GT, despite similar percentages of WASp-expressing cells and gene marking as those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), IL-10 producing regulatory B cells (Bregs), and transitional B cells. Recovery of the Breg compartment, along with Tregs, thus appears to be protective against development of autoimmunity post-GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered with ClinicalTrials.gov (NCT01410825).