Clinical Efficacy of Gene Therapy for Severe Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is a complex immune disorder of genetic origin. Symptoms of classical WAS include recurrent infections, bleeding, atopy, auto-immunity and lymphoreticular malignancy. The high morbidity associated with hematopoietic stem cell (HSC) transplantation from partially matched donors has prompted the search for alternative strategies based on gene-corrected autologous HSCs. A lentiviral vector incorporating endogenous regulatory sequences was used to transduce either autologous bone marrow-derived or mobilized peripheral blood HSCs in six severely affected WAS patients with an age range of 0.8 to 15.5 years. Following engraftment, five out of the six patients are alive and show sustained clinical benefit eighteen to thirty-six months after treatment. They exhibit high-level and stable engraftment of functionally corrected lymphoid cells promoted by an in vivo growth and survival selective advantage. Persistence of myeloid cell engraftment and platelet correction correlated more with the administered dose of gene-corrected cells. No sign of vector-related toxicity has been observed by clinical assessment, and vector integration site analysis demonstrates sustained polyclonal engraftment in all patients. Gene therapy based on refined vector design is therefore an effective and well tolerated therapeutic option in patients with severe WAS, and has potential to become a standard of care for patients without matched HSC donors.