An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay–Sachs or Sandhoff variants)

• Published in: Molecular genetics and metabolism Vol. 102; no. 1; pp. 6 - 12
• Main Authors: Clarke, Joe T.R., Mahuran, Don J., Sathe, Swati, Kolodny, Edwin H., Rigat, Brigitte A., Raiman, Julian A., Tropak, Michael B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2011
• Subjects: Adult; beta-Galactosidase - blood; Clinical trials; Drugs; Endoplasmic reticulum; Enzyme Assays; Enzymes; Female; Gangliosidoses, GM2 - drug therapy; Gangliosidosis; Glucosylceramidase - blood; GM2 gangliosidosis; Hexosaminidase A - blood; Hexosaminidase B - blood; Humans; Leukocytes; lysosomal storage diseases; Lysosomes; Male; Middle Aged; Mutation; Pharmacokinetics; Pharmacologic chaperone; Pyrimethamine; Pyrimethamine - adverse effects; Pyrimethamine - blood; Pyrimethamine - therapeutic use; Quality control; Side effects; Young Adult; GM2 gangliosidosis; Pharmacologic chaperone; Pyrimethamine
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2010.09.004

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the
HEXA (Tay–Sachs variant) or the
HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100
mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50
years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50
mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75
mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy.