Gene therapy of chronic granulomatous disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thir ds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form o f CGD bicistronic retroviral vectors containing the gp91-phox gene and a se lectable marker gene were constructed, The ability of these vectors to rest ore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34(+) cells obtained from X-CGD patients. tinder optimal conditions 80% of the CD 34(+) cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced c ells was 68.9% of normal levels, Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present exp eriments provide the basis for the development of a gene replacement therap y for the X-linked form of CGD.