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)

Abstract

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initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related.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.

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

“…1f) 19 as an inhibitor of the wild-type enzyme. Pyrimethamine chaperones disease-causing mutant proteins in cells and has since entered phase I and II trials for treatment of GM2 gangliosidosis 34 . In addition to class selectivity, one complication encountered in the development of glycoside hydrolase chaperones is that dosing in trials must be tuned to favor chaperoning over inhibition.…”

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene

“…As it is the case in many lysosomal diseases, the severity and onset of G M2 gangliosidosis inversely correlates with the residual rate of G M2 catabolism. Specifically, in infantile Tay-Sachs and Sandhoff patients the residual G M2 conversion rate does not exceed 0.5%, in juvenile and adult forms it reaches 2–4% of normal, while the residual rates above about 10% of normal seem to be compatible with the healthy state [32], [33]. Interestingly, the three recently reported patients homozygous for p.P55L in GM2AP presented with a neurological movement disease without ocular features and an onset at the age of 7–8 years [9].…”

Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity

“…3 The observed increase in Hex A activity levels in patients' leukocytes (up to a maximum of 4-fold) was closely correlated with their plasma levels of PYR, which varied according to the oral dose of the drug (25, 50, 75, or 100 mg/ day) and the metabolism of each patient; i.e., patients taking the same dose could have very different levels of plasma PYR. As an anti-malarial, PYR has 1000-fold higher affinity for the parasite versus human DHFR.…”

“…2 Indeed, we have shown that, in some late-onset forms of GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases), the Hex A activity in patient fibroblasts can be enhanced by 2−3-fold. 3 Recently it has been reported that treating Dutch APP E693Q mice (a mouse model of Alzheimer's disease) with a PC for Hex dramatically reduced the accumulation of a β-amyloid peptide:ganglioside (GM2 and GM3) complex. This reduction was associated with improved learning behavior and decreased anxiety in the treated mice.…”