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Acta Haematol. 2003;110(2-3):86-92.

Gene therapy for chronic granulomatous disease.

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Herman B Wells Center for Pediatric Research and Department of Pediatrics (Hematology/Oncology), James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.


Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory burst NADPH oxidase, the enzyme complex required for the production of reactive oxygen intermediates in phagocytes. The absence of phagocyte oxidants results in a predisposition to recurrent bacterial and fungal infections and inflammatory granulomas in CGD patients, associated with significant morbidity and mortality. Allogeneic bone marrow transplantation can cure CGD, but transplant-related toxicity and the limited availability of matched donors have restricted its wider application. Because the gene defects causing CGD are known, and CGD is a stem cell disorder treatable by marrow transplantation, CGD has emerged as a promising disease for somatic gene therapy targeted at the hematopoietic system. Multiple reports have demonstrated the reconstitution of NADPH oxidase activity by gene transfer to human CGD marrow and cell lines cultured in vitro. CGD mouse models have been developed by gene disruption, and preclinical studies on these animals using recombinant retroviral vectors have demonstrated reconstitution of functionally normal neutrophils and increased resistance to pathogens such as Aspergillus fumigatus, Burkholderia cepacia and Staphylococcus aureus. Although the results of these murine studies are encouraging, human phase-I clinical studies in CGD patients have yet to produce clinically beneficial numbers of corrected neutrophils for extended periods. Efforts to improve gene transfer efficiency into human hematopoietic stem cells and to increase engraftment of transduced stem cells are ongoing.

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