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)


Principal Investigators: 

Dr. J.T.R. Clarke, MD, PhD   Senior Associate Scientist, Hospital for Sick Children Research Institute, Professor (Pediatrics), University of Toronto, Ontario, Canada

Dr. Don Mahuran, PhD, Senior Scientist, Hospital for Sick Children Research Institute, Professor (Laboratory Medicine & Pathobiology), University of Toronto, Ontario, Canada

Edwin H. Kolodny, MD, Professor of Neurology, New York University School of Medicine, Neurogenetics Unit, NY, USA

Clinical Research Project Manager:

Mohammed Hussain, Ontario Lysosomal Storage Disease Coordinator


Project Purpose and Objective:

Adult Tay-Sachs disease and Sandhoff diseases are caused by deficiency of an enzyme called beta-hexosaminidase A, or Hex A in short. This enzyme is located in a particular cellular component, called lysosomes, inside the brain cells. The reason that Hex A of patients with Adult Tay-Sachs disease or Sandhoff disease is deficient is because this enzyme had gone through mutation, resulting in it not working very well. In healthy people, Hex A efficiently breaks down GM2-ganglioside, which is a by-product from cells of our body. However, patients with Adult Tay-Sachs disease or Sandhoff disease cannot efficiently break down GM2-ganglioside in the body. Therefore, these patients have high levels of this by-product in the brain cells, which causes the brain to be unable to function normally.


Pyrimethamine is a Health Canada approved anti-malarial and antitoxoplasmosis drug used specifically in the treatment of active, chloroquine-resistant malaria. It has been found to be a specific Hex Aenzyme inhibitor, chosen based on screening of 1,040 FDA-approved compounds from the chemical library of the National Institute of Neurological Disorders and Stroke (NINDS) for inhibitors of Hex Aenzyme activity. Accordingly, it can be used to increase the Hex Aenzymatic activity in Adult Tay-Sachs and Sandhoff disease via the PC-approach.



The efficacy of Pyrimethamine in the treatment of chronic GM2-Gangliosidosis (Tay-Sachs or Sandhoff variants) has been investigated in a number of cell culture studies, using cell lines from various patients affected with Adult Tay-Sachs or Sandhoff disease. The results of thesestudies, have been published in the Journal of Biological Chemistry (Maegawa et al., 2007). In these in vitro and cell culture studies, a Pyrimethamine concentration range of 0.1-3 ?g/mL was used. This concentration range was choosen because Pyrimethamine, when used to treat central nervous system (CNS) toxoplasmosis in immunocompromised patients, reached levels in the cerebral-spinal fluid (CSF) of 0.15-0.46 ?g/mL.

If Hex A can function normally in presence of Pyrimethamine, this drug should be able restore the brain malfunction of these patients since Hex A can now efficiently break down GM2-ganglioside with Pyrimethamine treatment.

The objective of this study is to see if Pyrimethamine is safe in these patients and to see if it can restore the brain function of these patients.

The objectives of this Phase I/II clinical trial are to assess the safety and tolerability, as well as efficacy, of a stepwise dosing regimen of pyrimethamine, starting at 25 mg/day, given as a single dose daily for 4 weeks, then increasing by 25 mg per dose in three four-week steps, to a final dose of 100 mg/day, in patients affected with chronic GM2-gangliosidosis (Tay-Sachs or Sandhoff variants).  Safety and tolerability will be assessed based on conventional laboratory and clinical assessments, whereas efficacy will be assessed based on changes in ?-hexosaminidase A and B activities in plasma and peripheral blood leukocytes.



Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.

Authors: Maegawa GH, Tropak M, Buttner J, Stockley T, Kok F, Clarke JT, Mahuran DJ.

J Biol Chem. 2007 Mar 23;282(12):9150-61. Epub 2007 Jan 21.