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

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_F responsiveness
in CGD based on mutational analysis. compare the change in function of the NADPH oxidase
during treatment with an escalating dose of IFN_ompasubjects 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_R 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 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 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.