Infantile Neronal Ceroid Lipofuscinosis Clinical Trial
Official title:
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 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. ;
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment