Biomarker Validation for Niemann-Pick Disease, Type C: Safety and Efficacy of N-Acetyl Cysteine

Niemann-Pick Disease, type C (NPC) is an autosomal recessive lysosomal storage disease with progressive neurodegeneration. It is characterized by intracellular accumulation of cholesterol and glycosphingolipids. The age of onset is variable with cases manifesting from infancy to adulthood. Classically, initial neurological symptoms are observed in early to late childhood. Symptoms and signs of NPC include prolonged neonatal jaundice, splenomegaly, and various neurological manifestations, especially ataxia, dysmetria, dysarthria, vertical supranuclear gaze palsy and cognitive decline. Currently there are no approved therapies for NPC. A recent controlled study and a series of case reports suggest some efficacy for miglustat. Miglustat inhibits the biosynthesis of glycosphingolipids. The pathophysiological processes contributing to neurodegeneration in NPC have been intensively studied in NPC mouse models. Potential pathological processes include toxic effects of cholesterol or glycosphingolipid accumulation, deficient oxysterol production, peroxisomal dysfunction, mitochondrial dysfunction, perturbed intracellular calcium homeostasis, inflammation, induction of apoptosis, deficient neurosteroid synthesis, and increased oxidative stress. The degree to which each of these pathological processes contributes to the pathology of NPC is not known; however, the multiple processes involved suggest that combinatorial therapy addressing various aspects of this disorder will be necessary. A major impediment to the development of clinical trials for NPC has been the prior lack of outcome measures. Identifying biomarkers was a major goal of our NPC natural history trial (06-CH-0186). We now have identified multiple biochemical abnormalities in our cohort of patients that may prove useful as biomarkers in a therapeutic trial. The next step is to attempt to validate these potential biomarkers in a therapeutic trial. Thus in this protocol we plan to evaluate the safety and efficacy of N-acetylcysteine to improve a group of biomarkers related to increased oxidative stress.

The goals of this protocol are:

• To validate the use of biomarkers in a therapeutic trial for NPC.
• To evaluate the safety of N-acetylcysteine in NPC patients.
• To evaluate the efficacy of N-acetylcysteine to improve biomarkers associated with increased oxidative stress in NPC patients.

• INCLUSION AND EXCLUSION CRITERIA:

All patients with an established diagnosis of NPC will be considered for this study. The diagnosis may be based upon either molecular or biochemical testing.

Inclusion criteria

• Diagnosis of NPC by cellular assay or molecular testing.
• Twelve months of age or older and weight greater than 10 kg.
• Patient must be able to take the study medication orally or per gastrostomy tube.

Exclusion criteria

• Patients will be excluded if they cannot travel to the NIH because of their medical condition or are too ill to be cared for at home.
• Patients will be excluded if they are unable to tolerate the study procedures.
• Patients will be excluded if they are pregnant (a negative urine pregnancy test will be required for any menstruating female before participation in this study and at each NIH Clinical Center admission). If sexually active, contraception must be used for the duration of the study.
• Patients will be excluded if they have had prior allergic or hypersensitivity symptoms associated with NAC use.
• Patients will be excluded from the study if they are unwilling to discontinue the following drugs and supplements for the duration of the study.

• a. All dietary supplements
• b. Any antioxidant supplement other than prescribed by the study. This will include dietary juices or drinks being marketed as a source of antioxidants
• c. CoQ10 supplements
• d. Any over-the-counter medication being used on a daily basis for which there is not a defined clinical reason
• e. NAC use
• Physician prescribed medications will be reviewed on a case-by-case basis. Patients may be excluded if medical therapies could interfere with the study endpoints. Except for carbamazepine, seizure control medications will be allowed. Patients will be excluded if taking carbamazepine or nitroglycerin.
• Over-the-counter medications use on a daily basis will be reviewed on a case-by-case basis. Patients may be excluded if medical therapies could interfere with the study endpoints.
• Patients will be excluded if they have an uncontrolled seizure disorder.
• Patients on miglustat at the start of the study will be excluded if the dose of miglustat cannot be held constant for the duration of the study. The miglustat dose must have been constant for two months prior to the baseline NIH evaluation. Patients will be withdrawn if they initiate miglustat use after entering the study.
• Patient who are at risk for gastric hemorrhage (preexisting esophageal varices or peptic ulcer disease).
• Patients on a sodium restricted diet for medical reasons.
• The following laboratory test abnormalities will exclude patients from the study:

• a. AST or ALT elevated greater than 4-fold upper limit of normal. Note: NPC patients frequently have transaminase levels 2-3 fold above normal.
• b. Anemia defined as two standard deviations below normal for age and gender.
• c. Platelet count less than 75,000.
• d. Elevated serum creatine level
• e. Hematuria or proteinuria