Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease

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.

• INCLUSION CRITERIA:

Subjects may be enrolled if they are:

1. Already are enrolled on an existing CGD protocol at the Clinical Center (and will remain enrolled on their existing protocol);
2. Are included in one of the study cohorts listed below;
3. Male or female;
4. Able to comply with self-administration of a subcutaneous injection; and
5. Willing to have their blood samples stored for the duration of this study and for future research.

Study Groups/Cohorts:

X-linked CGD Nonsense/Frameshift/RNA Processing/Deletion Mutations Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented nonsense, frameshift, RNA processing, or deletion gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

X-linked CGD Missense Mutation with Low Baseline Superoxide Production (less than or equal to 2.5 nmol/10(6) cells/hr) Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented missense gene and superoxide production by cytochrome c reduction assay at baseline of less than or equal to 2.5 nmol/10(6) cells/hr. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

X-linked CGD Missense Mutation with Higher Baseline Superoxide Production (greater than 2.5 nmol/10(6) cells/hr) Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented missense gene and superoxide production by cytochrome c reduction assay at baseline of greater than 2.5 nmol/10(6) cells/hr. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

Autosomal Recessive p47phox CGD Cohort: Subjects in this cohort must have autosomal recessive CGD resulting from a documented p47phox gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

Autosomal Recessive p67phox CGD Cohort: Subjects in this cohort must have autosomal recessive CGD resulting from a documented p67phox gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

EXCLUSION CRITERIA:

Subjects are excluded from the study who:

1. Have undergone successful bone marrow transplantation;

2. Had a serious adverse reaction to IFN gamma in the past;

3. Are pregnant or breast feeding;

4. Weigh less than 11 kg;

5. Are currently on therapy with INF gamma;

6. Have any of the following medical conditions:

   • Coronary artery disease;
   • Hepatic disease and/or liver enzymes elevated above 3 times normal;
   • Seizure disorder, or
   • Severe myelosuppression (absolute neutrophil count less than1000 cells/mm(3)).

Participation of Minors: minor patients will be invited to participant in this study.

Participation of Women: Exposure to IFN gamma by the developing human fetus may be detrimental. For this reason, women of childbearing-age will have a pregnancy test prior to undergoing study procedures. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should immediately inform study staff and her primary care physician.

Pregnancy and Lactation: The effects of IFN gamma therapy on the developing fetus and newborn infant have not been studied. Therefore, it is not recommended that subjects who are pregnant or breast-feeding receive IFN gamma and they will be excluded from this study.