CGD - Chronic Granulomatous Disease Clinical Trial
Official title:
Assessment of the Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
Background:
- 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.
Objectives:
- To compare changes in the immune system caused by interferon-gamma treatment for CGD in
individuals with different mutations that cause CGD.
Eligibility:
- Individuals of any age who have been diagnosed with CGD and have specific types of
mutations that cause CGD (to be determined after testing).
Design:
- 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 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.
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