Gene therapy for chronic granulomatous disease.

Mutations in phagocyte NADPH oxidase cause CGD, resulting in recurrent infections and granulomatous inflammation. Hematopoietic stem cell (HSC) transplant can cure CGD, but most patients lack a suitable donor. We conducted a clinical trial of ex vivo autologous HSC gene transfer as salvage therapy for three patients with X-linked CGD (X-CGD) who had incurable infection. Patients received nonmyeloablative busulfan conditioning and then were infused with amphotropic MFGS-gp91phox murine retrovirus vector-transduced autologous HSC, resulting in early gene marking and high-level oxidase function correction of 24%, 5%, and 4% of circulating neutrophils. Subjects #1 and #3 fully resolved infection and have maintained gene marking at 5 years at 0.7% and 0.03% oxidase-normal neutrophils. Subject #2 lost gene marking by 4 weeks and at 6 months succumbed to his infection. The two surviving subjects have normal blood count and bone marrow exam, with no evidence for clonal dominance of vector inserts. We conclude that gene therapy salvage treatment for severe infection unresponsive to conventional therapy can provide life-saving clinical benefit to CGD patients lacking a suitable donor. We are developing lentivectors for our next generation gene therapy of CGD. We are also exploring novel alternate approaches to gene therapy using zinc finger nuclease-mediated gene targeting of induced pluripotent stem cells derived from CGD patients.