Chronic Granulomatous Disease (CGD) is caused by mutations of 1 of the 4 proteins comprising the NADPH oxidase that result in decreased or absent production of superoxide by phagocytes, and predisposes CGD subjects to life-threatening infection. Intensive management with antibiotics and antifungal agents has dramatically increased the life expectancy of subjects with CGD. Interferon-gamma (IFN gamma), which increases superoxide production by neutrophils and enhances their antimicrobial activity, is an FDA approved therapy for CGD and is now the standard of care. However, there is substantial variability in the biochemical and clinical response to IFN gamma treatment. Recently, the specific mutations of the genes responsible for causing CGD in most of the subjects followed at the NIH have been characterized. Because of this, it is now known that the severity of the disease is correlated not only with inheritance pattern, but also with the specific underlying mutation. It is not known, however, if the biochemical response to IFN gamma therapy correlates with the specific mutation as well.
Since treatment with IFN gamma is expensive, requires frequent injections, and in some subjects results in systemic side effects, it would be useful to determine whether the biochemical response and systemic side effects correlate with the underlying mutation GCD.
We hypothesize that subjects with X-linked CGD due to nonsense/frameshift/RNA processing/deletion mutations of the gp91phox component of the NADPH oxidase will generate a smaller biochemical response to IFN gamma therapy compared to subjects with missense gp91phox mutations or the autosomal recessive form of CGD that results from mutations of the p47phox or p67phox components.
The primary objective of this study is to assess the predictability of IFN gamma responsiveness in CGD based on mutational analysis. compare the change in function of the NADPH oxidase during treatment with an escalating dose of IFN gamma in subjects with CGD resulting from missense or nonsense/frameshift/RNA processing/deletion gp91phox mutations or mutations of p47phox or p67phox. The secondary objectives are to assess changes in superoxide production, expression of NADPH oxidase components, neutrophil bactericidal capacity for Staphyloccus aureus, cytokines, cell surface markers, antibodies, lymphocyte subsets, constitutional symptoms , and gene expression in leukocytes from subjects with missense gp91phox mutations, nonsense/frameshift/RNA processing/deletion gp91phox mutations, p47phox mutations, and p67phox mutations after treatment with IFN gamma to assess changes in the expression of NADPH oxidase components, cytokines, cell surface markers, antibody production, production of various lymphocyte subsets, constitutional symptoms and gene expression in leukocytes from these subjects following treatment with IFN gamma. This knowledge will assist physicians in determining which subjects are likely to respond to full dose and alternative dose therapy with IFN gamma and provide information about biochemical responses of to these regimens in subjects with specific CDG gene mutations enabling them to better counsel and manage subjects with CGD.
