Abstract

Chronic granulomatous disease (CGD) is a congenital immune deficiency that is a promising therapeutic target for gene replacement into haematopoietic stem cells (HSCs). CGD results from mutations in any one of four genes encoding subunits of the superoxide-generating NADPH oxidase of phagocytes. Life-threatening, recurrent bacterial and fungal infections, as well as inflammatory granulomas, are the hallmarks of the disease. NADPH oxidase activity can be reconstituted by retroviral- or lentiviral-mediated gene transfer to human CGD marrow in vitro and in xenograft transplant models. Gene transfer studies in knockout mouse models that resemble the human disease suggest that correction of oxidase activity in a minority of phagocytes will be of clinical benefit. Phase I clinical studies in unconditioned CGD patients showed transient expression of small numbers of gene-corrected neutrophils. Areas of research at present include efforts to enhance gene transfer rates into repopulating HSCs using vectors that transduce quiescent cells, and to increase the engraftment of genetically corrected HSCs using non-myeloablative conditioning and drug resistance genes for selection.