Leading the worldwide fight to treat and cure
Tay-Sachs, Canavan, GM1 and Sandhoff diseases

2009 Research Initiative Grants

Joe Clarke, MD, PhD, Hospital for Sick Children /
Edwin Kolodny, MD, New York University

Proposed Investigator-Initiated Clinical Trial
of Pyrimethamine as a Treatment for
Late-Onset GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)


The present study was undertaken to examine the potential clinical benefit of the treatment of late-onset forms of both Tay-Sachs Disease- and Sandhoff Disease-variants of GM2 gangliosidosis with pyrimethamine (PYR). The Phase I/II clinical trial focused on the establishment of the tolerability of the treatment and indications of efficacy based on measurements of leukocyte Hex A activity, and the levels of PYR in patients’ plasma.


GM2 gangliosidosis (GM2) is an inherited neurodegenerative disorder caused by deficiency of lysosomal β-hexosaminidase A (Hex A). In the late-onset patients, only a low level of Hex A activity is needed to prevent or reverse the excessive substrate storage. Pharmacological chaperones (PC) have been found to stabilize the native folding the enzyme, resulting increased enzyme concentration in lysosome.

PYR was identified as such a pharmacological chaperone for Hex A. However, the clinical benefit of PYR has yet to be established and the safety profile is unclear. This project provided the critical information by clinically testing PYR as potential therapeutic agents for GM2 patients.

Future work:

The results showed increased Hex A activity with increasing PYR concentration in plasma, which was consistent with the preclinical study results. The pharmacokinetics of the drug varied considerably with subjects. Adverse drug reactions wee observed in patients at high doses. Further studies are necessary to evaluate the effect of the treatment and to optimize the benefits to the individual patients.

Link to resulting publication at PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/20926324

Florian Eichler, MD
Massachusetts General Hospital

A Biomarker for Disease Progression in
GM2 and Other Neurolipidoses


The goal of this study was to develop Magnetic Resonance Imaging (MRI) based biomarkers using advanced imaging techniques. The scientists discovered the ability to use perfusion MR techniques to quantify cerebral blood flow changes in adrenoleukydystropy (ALD) patients. The data indicated that regional decrease of blood volume is an early sign of lesion progression.


Neurolipidoses are genetic disorders in which lipids accumulate within the nervous system. Individual disorders exhibited marked variation in regional neuropathology. And the evolution in the context of the patient’s natural history remained poorly understood. The scientists proposed developing a MR based biomarker by measuring regional brain metabolism in ALD patients.

The biomarker, if established, will help decide optimal timing of intervention and assess efficacy of novel treatments in clinical trials. Unfortunately, the observations on the metabolic abnormalities in late-onset GM2 gangliosidoses did not reach significance. The challenge remains to establish a large enough sample size in future work.

Alexey Pshezhetsky, PhD
Universitey of Montreal

Novel Therapy for Tay-Sachs Disease,
Sialidosis and Ggalactosialidosis
Using a Metabolic Bypass Catalyzed
by the Lysosomal Sialidase Neu4


The present study assessed whether Neu4 is the enzyme responsible in vivo for the metabolic bypass of the HexA defect in the mouse model of Tay-Sachs disease by studying mice with a double deficiency of Neu 4 and Hex A.


Tay-Sachs disease is a lysosomal storage disorder, caused by mutations in the gene coding for lysosomal β-hexosaminidase A (HexA), resulting in accumulation of GM2 ganglioside in neurons followed by progressive neurologic degeneration, fatal in early childhood. However mice, depleted of HexA, remain asymptomatic up to at least one year of age, owing to the ability of these mice to catabolize stored GM2 ganglioside via a lysosomal neuraminidase, thereby bypassing the HexA defect.

The current study provided an explanation why the disease is severe in humans but not in mice. It was showed that mice depleted of both HexA and ganglioside neuraminidase 4 (Neu4) show epileptic seizures similar to that often observed in Tay-Sachs patients. Single HexA or Neu4 knockout mice do not show such symptoms.

The results of the study revealed a novel mechanism in the mouse model of TS disease. Also the data suggested Neu4 as a potential pharmacologic modifier for the treatment of human Tay-Sachs disease.

Link to resulting publication at PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/20862357

Mark Sands, PhD
Washington University

Combination Therapy for Krabbe Disease


This study combined Bone Marrow Transplantation (BMT) with gene therapy for the treatment of Globoid-cell leukodystrophy (GLD, Krabbe disease), resulting in significant improvement in most outcome measures in mouse models.


GLD is an autosomal recessive disease caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC).  Bone Marrow Transplantation (BMT) was then the only available therapy for GLD. However, emerging data suggested that BMT only delayed the onset of disease.  Therefore, new, less invasive approaches were required to treat GLD.

Scientists in Sands lab set out to determine the efficacy of CNS-directed gene therapy (forebrain, cerebellum, and spinal cord) alone and in combination with BMT in the newborn murine model of GLD. They observed synergistic improvement in the combination-treated group from the experiment.

It was proposed that combination therapy using an AAV vector and BMT during the neonatal period is a viable approach for treating GLD.

Future work:

Future studies might further improve on this regimen by adding other therapies like substrate reduction, increasing bone marrow engraftment, increasing the number of donor-derived cells entering the brain, and using transduced bone marrow expressing high levels of enzyme.

Link to resulting publication at PubMed.gov: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348856/