336. Correction of Chronic Granulomatous Disease by Gene Therapy

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency characterized by recurrent and life-threatening bacterial and fungal infections. CGD is caused by mutations in any one of four genes encoding for subunits of the phagocytic NADPH oxidase complex. Most patients contain mutations or deletions within the gene coding for gp91phox, the larger subunit of the complex. Based on our preclinical work, two X-CGD patients, 26 and 25 years old, were treated with gene modified cells. G-CSF mobilized CD34+ cells were transduced with a monocistronic gp91phox retroviral vector. The transduction efficiency was 45% for Pat.1 and 40% for Pat. 2. The number of CD34+ cells reinfused was 1.210e7 per kg for Pat.1 and 0.910e7 per kg for Pat. 2. Before reinfusion, patients were treated with liposomal busulphan given i.v. at a dose of 4 mg/kg at two consecutive days, starting at day -3. The treatment was well tolerated and no adverse effects have been observed. Neutrophil counts declined to less than 100 cells per l at day 15 post reinfusion for both patients and recovered to more than 500 cells per l at day 30 for Pat. 1 and day 20 for Pat. 2. A significant fraction of gene marked cells has been detected in peripheral blood of both patients since day +21. Similarly, therapeutic relevant levels of NADPH oxidase activity have been observed since day +21. Both patients are well and have been free of severe bacterial and fungal infections since transplantation. Our data suggests that gene therapy is an option for the treatment of CGD, despite the fact that gp91phox corrected cells will not have per se a proliferative advantage over non-transduced cells.