• Slowing down or arresting the progression of neurodegeneration, control of seizure activity [ Designated as safety issue: No ]
  

Drug: Cystagon
N/A

Neuronal ceroid lipofuscinosis (NCLs) are the most common (1 in 12,500) heritable progressive encephalopathies of children. Infantile NCL (INCL) is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency. PPT catalyzes the hydrolysis of thioester linkages in S-acylated polypeptides and its deficiency causes abnormal accumulation of these polypeptides, leading to INCL. Since thioester bonds are susceptible to nucleophilic attack, drugs with nucleophilic properties may have therapeutic potential for INCL. Accordingly, we tested several compounds with nucleophilic properties (i.e., cysteamine, phosphocysteamine and N-acetylcysteine) and found that these drugs disrupt thioester linkages in a model high-energy thioester substrate, [(14)C] palmitoyl~CoA, releasing [(14)C] palmitic acid. As a positive control, we used hydroxylamine, a compound that specifically cleaves thioester linkages. Among the drugs tested, we characterized phosphocysteamine in further detail because: (i) INCL is a lysosomal storage disease and phosphocysteamine is reported to concentrate in the lysosomes; (ii) we found that phosphocysteamine functions at a low pH in cleaving thioester linkages; (iii) it crosses the blood-brain barrier; (iv) it prevents apoptosis in INCL lymphoblasts and (v) it is relatively nontoxic. Furthermore, our laboratory studies have shown that phosphocysteamine not only disrupts thioester linkages in S-acylated polypeptides in cultured cells from INCL patients but also mediates the depletion of intracellular ceroid deposits and prevents their reaccumulation. For the last 31/2 years we have been conducting a clinical trial to determine whether Cystagon is beneficial for INCL patients. So far, we have treated 6 Caucasian patients (3 females & 3 males). Our preliminary results indicate that Cystagon slows down the rapid neurodegeneration characteristic of INCL. Moreover, our patients have not developed epileptic seizures, a common complication of this disease. In fact, before the initiation of Cystagon treatment the EEG of one patient revealed epileptic foci, which were not detected in repeat EEG tests six months after treatment with this drug. The most dramatic effect of Cystagon is the complete clearance of lysosomal ceroids in WBCs within six months of therapy. In parallel with these studies, using an animal model of INCL we tested the effects of Cystagon alone and a combination of Cystagon and N-acetylcysteine (Mucomyst), which manifests anti-apoptotic and neuroprotective properties. Our preliminary results show that this combination therapy delays the development of neurological symptoms, reduces apoptosis and maintains the brain volume in these mice for a longer period of time compared with those treated with Cystagon alone. These preliminary results prompt us to propose a combination therapy with Cyatagon plus Mucomyst for INCL patients. Since INCL is a fatal disease and Mucomyst, has anti-apoptotic and neuroprotective effects, and since Mucomyst, like Cystagon, has a proven record of safety, we propose to test a combination of these two drugs in 20 INCL patients. In this population of 20 patients we will include those who are currently enrolled in our ongoing INCL-Cystagon study (#01-CH-0086).

• INCLUSION CRITERIA:

Only patients between 6 months and 3 years of age will be admitted in this study.

Patients should not require extensive medical or nursing care during their stay at the Clinical Center.

Patients who have a genetic diagnosis and carry any combination of two of the following specific PPT mutations: L10X, R151X, R164X, W296X, R122W, c.169insA and E184K.

Both male and females patients are eligible for enrollment in this study.

EXCLUSION CRITERIA:

Patients with intractable seizures that cannot be controlled by two or fewer antiepileptic medications will not be accepted for this study.

Patients who cannot take nourishment orally or who are in a vegetative state will not be enrolled in this study even if the 6 months to 3 year age criterion is met.