Gene therapy of chronic granulomatous disease (CGD) by gene transfer into hematopoietic stem cells.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency characterized by severe recurrent bacterial and fungal infections of several organs. The disease is due to the inability of phagocytic leukocytes to generate reactive oxygen species upon phagocytosis. The defect arises as a consequence of mutations of the genes encoding for the subunits of a membrane NADPH oxidase, which catalyzes the production of superoxide anion (O2-). CGD represents an ideal candidate disorder for gene therapy, since the disease has a recessive inheritance, its phenotype is exclusively expressed in phagocytic cells, and a partial correction is likely to be effective. Given the short half-life of mature phagocytes, the optimal target cell population for gene transfer is the pluripotent hematopoietic stem cell. Transduction of CD34+ hematopoietic progenitors with retroviral vectors carrying the cDNA of the defective gene results in the correction of the enzymatic defect in myeloid cells differentiated in vitro. Still, the effective development of a clinical gene therapy protocol for this disease will await a substantial improvement in our current technology for the identification and manipulation of hematopoietic stem cells, and in our understanding of their biological and molecular properties.