Intravenous Immune Globulin to Treat Hereditary Inclusion Body Myopathy
Condition: Hereditary Inclusion Body Myopathy
MeSH terms: Muscular Diseases; Distal Myopathies
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will evaluate patients with Hereditary Inclusion Body Myopathy (HIBM) and examine
      the effects of immune globulin (IG) treatment on muscle and muscle function. HIBM is a
      progressive neuromuscular disease that begins in early adulthood, primarily affecting limb
      muscles. It results from mutations of the gene that is responsible for producing sialic acid,
      a sugar normally found on the surface of certain proteins, including alpha-dystroglycan,
      which is involved in muscle function. Some patients with HIBM have decreased sialic acid on
      the alpha-dystroglycan protein, which may be the cause of their muscle weakness. IG is a
      protein in the blood that carries a large amount of sialic acid. This study will administer
      IG to patients with HIBM and determine if the sialic acid in IG is taken up by muscle cells
      in these patients and if it can restore some of their muscle function.

      Four patients with HIBM will be admitted to this study at the NIH Clinical Center for
      evaluation and IG treatment. The evaluation lasts about 1 month. After completing baseline
      studies (see below), patients receive two intravenous doses of immune globulin (on days 6 and
      7), followed by measurement of muscle strength 2 days later (day 9). They receive additional
      IG infusions on days 13, 20, and 27. A final set of tests is performed on day 29. Patients
      may leave the hospital on pass when no studies are being done.

      A patient's initial evaluation includes:

        -  History and physical examination, neurological examination, eye examination

        -  24-hour urine collection

        -  Blood tests on two separate days

        -  Photographs showing the extent of muscle affected

        -  Chest x-ray, electrocardiogram (EKG), and echocardiogram

        -  Two muscle biopsies, one before and one after the IG treatments. For this procedure, a
           small sample of muscle tissue is surgically removed for examination under the
           microscope.

        -  Muscle strength and endurance testing, including the following:

      The patient uses pulleys attached to machines that measure the strength of 24 different
      muscle groups

      The patient walks for 6 minutes and performs exercises

      To evaluate swallowing, the patient swallows a thick substance called barium

      The patient's tongue strength is measured using a specialized instrument.

      -Magnetic resonance imaging (MRI) of the muscles of the thigh or calf: MRI uses a magnetic
      field and radio waves to produce detailed pictures of organs and tissues. During the scan,
      the subject lies on a table in a narrow cylinder containing a magnetic field, wearing ear
      plugs to muffle loud noises that occur with electrical switching of the magnetic fields. He
      or she can speak with a staff member via an intercom system at all times during the
      procedure.

      The neurological and muscle strength and endurance evaluations are repeated on study days 9
      and 29.
    

Detailed description: 
      Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive neuromuscular disorder
      with onset in early adulthood and progressive muscle weakness leading to death within 2-3
      decades. The causative gene, GNE, codes for the bifunctional enzyme UDP N-acetylglucosamine
      2-epimerase/N-acetylmannosamine kinase; mutations on both GNE alleles, in either or both the
      epimerase and kinase domains, can result in HIBM. Members of an Iranian-Jewish isolate are
      homozygous for a specific kinase domain mutation. The epimerase and kinase enzymes catalyze
      the first and second, rate-limiting steps in the synthesis of sialic acid, also called
      N-acetylneuraminic acid. This charged sugar provides the terminal carbohydrate on a variety
      of N-linked and O-linked glycoproteins that mediate cell-cell and protein-protein
      interactions. The cells of HIBM patients produce reduced amounts of free sialic acid, as
      evidenced by decreased sialylation of glycoproteins, including a critical muscle protein
      called alpha-dystroglycan (alpha-DG). This protein, decorated with O-mannosyl glycans
      containing a terminal sialic acid, is part of the dystrophin-glycoprotein complex responsible
      for linking the inside of muscle cells with the extracellular matrix. In HIBM, improper
      sialylation of alpha-DG, due to decreased sialic acid synthesis, is considered to impair the
      interactions of alpha-DG with its protein ligands, resulting in gradual deterioration of
      muscle cells. In this open-label pilot study, we propose to provide free sialic acid to
      muscle cells of HIBM patients by intravenous infusions of immune globulin (IvIg), a
      glycoprotein that contains 8 microlitermoles of sialic acid per gram and that has a proven
      safety profile as an FDA-approved drug. Four subjects will be treated - two homozygous for
      the Iranian Jewish kinase domain mutation, and two with at least one epimerase domain
      mutation. IvIg will be given as a loading dose of 1 gram per kilogram body weight on two
      consecutive days, followed each of the next 3 weeks by maintenance doses of 400 milligram per
      kilogram body weight. This should maintain the serum immune globulin level high enough to
      achieve continuous breakdown of large amounts of the glycoprotein, providing free sialic acid
      to the blood, scavenger cells and, we hope, muscle cells. Muscle biopsies and strength
      testing will be performed before and after the infusions. The primary clinical outcome
      parameter will be muscle strength, gauged mechanically by Quantitative Muscle Testing and
      manually by physical examination performed by a neurologist. Secondary outcome parameters
      will employ the 6-minute walk test, grip strength, tongue strength, swallowing duration, and
      the Human Activity Profile questionnaire. Staining of muscle beta-DG for sialic acid on
      O-mannosyl glycans will provide a histological outcome parameter. An improvement in muscle
      strength or alpha-DG sialylation will prompt a controlled trial of the efficacy of this
      treatment.
    

Intervention name(s): Immune Globulin
Intervention type(s): Drug
Intervention MeSH terms: Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin
Primary purpose: Treatment
Keywords: GNE Gene; Alpha-Dystroglycan; Sialic Acid; Glycosylation; Dystroglycanopathy; Hereditary Inclusion Body Myopathy; Immune Globulin; HIBM