Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
Condition: IFN-Gamma Therapy; CGD Gene Mutation; CGD Response to IFNg; CGD - Chronic Granulomatous Disease; Immunodeficiency Disease
MeSH terms: Granuloma; Granulomatous Disease, Chronic; Immunologic Deficiency Syndromes
Intervention: IFN-gamma
Intervention description: Following a washout period subjects have a subcutaneous injection of 50 mcg per meter squared once per week, Monday, for 4 weeks, twice per week, Monday and Thursday, for 4 weeks, then thrice per week, Monday, Wednesday, Friday, for 4 weeks. Total treatment period is 12 weeks.
Intervention MeSH terms: Interferons; Interferon-gamma
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Dose frequency increased from once per week to three times per week, the recommended dose frequency.
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Healthy volunteers: No
Keywords: NADPH Oxidase-Nicotinamide Adenine Dinucleotide Phosphate; Chronic Granulomatous Disease; Gene Mutation; Superoxide by Phagocytes; Interferon-Gamma

Summary:

      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.
    

Eligibility criteria:

        -  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.