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- Chronic granulomatous disease (CGD) is an immunodeficiency disease in which white blood cells are unable to kill certain bacteria and fungi. People with CGD are more likely to develop recurrent life-threatening infections. Certain changes or mutations in genes contribute to the severity of CGD, and also appear to affect the success of treatment with interferon-gamma, a substance that is used to improve the immune system's ability to fight infection. Researchers are interested in studying changes in the immune system caused by interferon-gamma treatment of CGD in individuals with different mutations that cause CGD.
- To compare changes in the immune system caused by interferon-gamma treatment for CGD in individuals with different mutations that cause CGD.
- Individuals of any age who have been diagnosed with CGD and have specific types of mutations that cause CGD (to be determined after testing).
- Participants will be screened with a medical history, physical examination, and blood and urine tests. Participants must weigh more than 11 kilograms (~24 pounds) to participate in the study.
- Participants will receive injections of interferon-gamma once weekly for 4 weeks, twice weekly for 4 weeks, and then three times weekly for 4 weeks (a total of 24 injections).
- Blood will be drawn periodically during treatment and for 8 weeks after the treatment, for a total of 21 weeks on the study. Participants will regularly provide information on their symptoms and responses to treatment to the study researchers.
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 and whether an alternate dosing regimen may be appropriate for some subjects.
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 IFNg 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 compare the change in function of the NADPH oxidase during treatment with an escalating dose of IFNg 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 the expression of NADPH oxidase components, cytokines, cell surface markers, antibody production, production of various lymphocyte subsets, and gene expression in leukocytes from these subjects following treatment with IFNg. This knowledge will assist physicians in determining which subjects are likely to respond to full dose and alternative dose therapy with IFNg and provide information about biochemical responses to these regimens in subjects with specific CDG gene mutations enabling them to better counsel and manage subjects with CGD.
Allocation: Non-Randomized, Control: Dose Comparison, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
National Institutes of Health Clinical Center, 9000 Rockville Pike
National Institutes of Health Clinical Center (CC)
Published on BioPortfolio: 2014-08-27T03:12:48-0400
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