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Gene therapy for chronic granulomatous disease.

Recent progress in the development of gene therapy for chronic granulomatous disease (CGD), an inherited immunodeficiency syndrome, is reviewed. This disorder results from defects in any of the four genes encoding essential subunits of respiratory burst oxidase, the superoxide-generating enzyme complex in phagocytic leukocytes. The absence of respiratory burst oxidants results in recurrent bacterial and fungal infections and can also be complicated by the formation of inflammatory granulomas. Although current management, including prophylactic use of antimicrobial agents and interferon-gamma, has significantly improved its prognosis, CGD continues to be associated with significant morbidity and mortality from life-threatening infections and complications. Allogeneic bone marrow transplantation can provide a life-long cure of the disease, but difficulty in finding suitable donors and risks associated with this procedure have limited its application. Recently CGD has emerged as a promising candidate for gene therapy targeted at the hematopoietic system. CGD mouse models have been developed with gene targeting technology, and preclinical studies in these animals with recombinant retroviral vectors have demonstrated the appearance of functionally normal neutrophils and increased resistance against pathogens such as Aspergillus. Although the murine studies have provided a promise of long-term cure of patients by gene transfer, phase I clinical studies in a limited number of patients with CGD with such vectors have yet to produce a clinically relevant number of corrected neutrophils for extended time periods. Efforts are ongoing to improve gene transfer efficiency into human hematopoietic stem/progenitor cells and to achieve better engraftment of the gene-corrected stem cells.