Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis
| Status: | Archived |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 7/1/2011 |
A Combination Therapy With Cystagon and N-Acetylcysteine for INCL Patients
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.
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 fatty-acylated-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 and N-acetylcysteine disrupt thioester linkages in
a model PPT1-substrate, [14C] palmitoyl~CoA, releasing [14C] 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 8 years, we have been
conducting a clinical trial to determine whether Cystagon (Cysteamine bitartrate) is
beneficial for INCL patients. In parallel with these studies, using an animal model of INCL
we found that there is high level of reactive oxygen species (ROS) generated in the brain of
mice lacking the PPT1 enzyme. ROS has been shown to cause damage to normal neurons. Both
Cystagon and mucomyst in addition to possessing nucleophilic property are antioxidants and
scavengers of ROS. Thus, in our current protocol we use a combination of Cystagon and
Mucomyst. We admitted a total of 10 patients (5 females and 5 males) to this protocol.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
301-496-2563
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
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