Document Detail

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).
MedLine Citation:
PMID:  20926324     Owner:  NLM     Status:  MEDLINE    
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initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related.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.
Joe T R Clarke; Don J Mahuran; Swati Sathe; Edwin H Kolodny; Brigitte A Rigat; Julian A Raiman; Michael B Tropak
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't     Date:  2010-09-17
Journal Detail:
Title:  Molecular genetics and metabolism     Volume:  102     ISSN:  1096-7206     ISO Abbreviation:  Mol. Genet. Metab.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-10     Completed Date:  2011-04-25     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  9805456     Medline TA:  Mol Genet Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6-12     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
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MeSH Terms
Enzyme Assays
Gangliosidoses, GM2 / drug therapy*
Glucosylceramidase / blood
Hexosaminidase A / blood
Hexosaminidase B / blood
Middle Aged
Pyrimethamine / adverse effects,  blood,  therapeutic use*
Young Adult
beta-Galactosidase / blood
Grant Support
82944//Canadian Institutes of Health Research
Reg. No./Substance:
58-14-0/Pyrimethamine; EC; EC; EC A; EC B

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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