? Adult Tay-Sachs (TSD) and Sandhoff disease (SD) result from a deficiency of lysosomal heterodimeric ?-hexosaminidase A (Hex A, a?). These disorders are characterized by progressive neurological deterioration that mainly affects motor, cerebral and spinocerebellar function. They affect fewer than 1000 people in the United States. There is no effective treatment for these diseases. ? ? Substantial evidence supports a disease model for TSD and SD which attributes pathology to decreased or absent Hex A levels in neuronal lysosomes of the brain. The problem in GM2-gangliosidosis is the inability of the cell to metabolize GM2 gangliosides. When the residual activity of Hex A falls below a critical threshold level, GM2 ganglioside influx into the lysosome (the site of Hex A activity) exceeds the degradation rate and excess substrate continuously accumulates. Consequently, the lysosomes increase in size and number, giving rise to a storage disease. ? ? The majority of the mutations in Hex A affect the ability of the enzyme to obtain and/or retain its native 3-dimensional fold in the endoplasmic reticulum (ER) where intracellular quality control is performed to retain and degrade defective enzymes. Pharmacological chaperones are small molecules that can stabilize the native conformation of a mutant enzyme in the ER and allow it to escape the ER's quality control system and its associated degradation pathway (ERAD). PCs have the potential to act as drugs when they can stabilize the native conformation of a mutant enzyme. ? ? In 2006, ExSAR applied for orphan drug designation from the FDA for pyrimethamine for the treatment of patients affected with late-onset GM2-gangliosidosis. The application is pending the positive outcome of clinical trials. Pyrimethamine is an FDA-approved drug which readily passes the blood- brain barrier (BBB). It is currently used to treat malaria and toxoplasmosis. The investigator's in vitro cell-based studies with fibroblasts from these patients show that pyrimethamine can function as a PC for Hex A and raise intracellular Hex A levels. Their hypothesis is that pyrimethamine administered to adult TSD and SD patients can improve neurological function and health. ? ? The investigator's objective in this application is to assess the safety and tolerability of the drug. They will conduct a Phase 1 trial using pyrimethamine to treat patients affected with GM2-gangliosidosis. Hex A and B (a?) activities in plasma and peripheral blood leukocytes will also be measured. The investigator's working hypotheses are that pyrimethamine administered according to the regimen of the trial will be tolerated and safe and result in increased Hex A levels in blood and brain. ? ? ?
