Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis
Condition: Infantile Neronal Ceroid Lipofuscinosis
MeSH terms: Neuronal Ceroid-Lipofuscinoses
Study type: Interventional
Phase: Phase 4

Summary: 
      This study will examine the effectiveness of a drug called Cystagon in treating infantile
      neuronal ceroid lipofuscinosis (INCL), a progressive neurological disease affecting children.
      At around 11 to 13 months of age, patients develop slowed head growth, mild brain atrophy
      (wasting), electroencephalographic (EEG) changes and retinal deterioration, with symptoms
      worsening over time. The disease results from an enzyme deficiency that causes fatty
      compounds called ceroid to accumulate in cells. In laboratory experiments, Cystagon has
      helped remove ceroid from cells of patients with INCL.

      Children with INCL between 6 months and 3 years of age may be eligible for this study.
      Participants take Cystagon daily by mouth every 6 hours. They are admitted to the NIH
      Clinical Center for a 4- to 5-day period every 6 months for the following tests and
      evaluations:

        -  Review of medical history, including a detailed record of seizures, physical
           examination, blood tests and clinical photographs. For the initial baseline studies,
           examinations may also be scheduled with pediatric neurology, ophthalmology and
           anesthesia services.

        -  Magnetic resonance imaging (MRI) of the brain MRI uses a powerful magnet, radio waves,
           and computers to provide detailed images of the brain without the use of X-rays. The
           patient lies on a table that slides inside a donut-shaped machine containing a magnetic
           field. The child requires general anesthesia for the procedure.

        -  Electroretinogram (ERG) measures the function of the retina, the light-sensitive tissue
           in the back of the eye. To record the flash ERG, a special contact lens is placed on the
           eye s surface and the eye is stimulated with flashes of light. Infants and very young
           children require general anesthesia for the procedure.

        -  Visual evoked potential (VEP) measures the function of the visual pathway from the eye
           to the brain. To record the VEP, five electrodes are placed on the scalp and the eye is
           stimulated with flashes of light. Infants and very young children must be anesthetized
           for the procedure.

        -  Electroencephalogram (EEG) measures brain electrical activity, using electrodes placed
           on the scalp. The test is useful in defining seizures. The child may need to be sedated
           to keep still during the test.

        -  Skin biopsy A small piece of skin is removed (usually from the upper arm or shoulder)
           under local anesthetic to grow cells in the laboratory. This procedure is done at the
           start of the study and is repeated after 1 year if therapy results are promising.

      Children s condition may improve, stabilize or worsen during this study. Life may be
      prolonged without significant improvement in quality. The information gained from the study
      may help scientists develop more potent drugs to treat INCL.
    

Detailed description: 
      Neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, represent a group of
      the most common (1 in 12,500) heritable neurodegenerative storage disorders of childhood.
      Mutations of at least 8 different genes are responsible for various forms of NCL. The
      infantile form of NCL or INCL is the most severe disease. It is caused by mutations in the
      palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 is a lysosomal enzyme that cleaves
      thioester linkages in S-acylated proteins and its deficiency leads to abnormal lysosomal
      accumulation of fattyacylated- proteins (ceroids) leading to INCL pathogenesis. Since
      thioester linkages are labile, drugs with nucleophilic property are likely to mimic PPT1 and
      may have therapeutic potential for INCL. We previously reported that cysteamine,
      phosphocysteamine, cysteamine bitartrate (cystagon) and N-acetylcysteine disrupt thioester
      linkages in a model PPT1-substrate, C(14) palmitoyl-CoA, releasing C(14) palmitic acid. The
      results of our laboratory studies have shown that cysteamine mediates the depletion of
      intracellular ceroid deposits and prevents their reaccumulation. For the last 9 years, we
      have been conducting a clinical trial to determine whether a combination of Cystagon
      (Cysteamine bitartrate) and N-acetylcysteine (mucomyst) is beneficial for INCL patients. In
      parallel with these studies, using an animal model of INCL we found that this combination
      therapy reduces oxidative stress caused by high levels of reactive oxygen species (ROS) in
      the brain of mice lacking the PPT1 enzyme. To date, we have admitted a total of 10 patients
      (5 females and 5 males) to this protocol; however, one male patient was lost to follow-up.
      Thus, we have treated 9 patients (5 females and 4 males) and these patients showed no adverse
      reactions to these drugs except for one patient who initially had mild gastrointestinal
      discomfort which went away when cystagon was stopped and restarted from the lowest dose and
      this mild adverse effect did not recur. Compared with the published natural history of INCL,
      our preliminary results show that although several parameters of disease progression are
      slowed due to the treatment it does not completely arrest the neurodegenerative process. We
      are currently analyzing all the data gathered so far and a manuscript describing the results
      will be prepared for submission to a peer-reviewed journal.
    

Intervention name(s): Cystagon
Intervention type(s): Drug
Intervention MeSH terms: Cysteamine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Palmitoyl-Protein Thioesterase; Lysosomes; Batten Disease; Encephalopathy; Progressive Neurodegeneration; CLN 1; Infantile Neuronal Ceroid Lipofuscinosis; Cystagon