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Leading the Fight to treat and cure
Tay-Sachs, Canavan, Sandhoff, GM1 and related diseases

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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)

Description:

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.

Impact:

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

Description:

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.

Impact:

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

Description:

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.

Impact:

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

Description:

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.

Impact:

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/

 

 

NTSAD's grants are sometimes made in collaboration with partners such as the NIH and other patient advocacy groups for the allied diseases.

These grants went on to receive over $10 million in funding through NIH!

Read about the braod array of research grants NTSAD has funded.

2016 Research Initiative Grants

2015 Research Initiative Grants

2014 Research Initiative Grant

2012-2013 Research Initiative Grants

2011 Research Initiative Grants

2010 Research Initiative Grants

2009 Research Initiative Grants

2008-2002 Grants

 

 

David Radin, PhD, Principal Investigator
BioStrategies, LC

Lectin-Assisted Transnasal Delivery of
Corrective Enzyme for GM1 Gangliosidosis

Description:

Radin and his coworkers tested the nasal administration of the in-house developed enzyme therapy in GM1 gangliosidosis mouse models. It was demonstrated that a small amount was detectable in the brain. However, the therapy was not delivered via olfactory nerves as designed, showed by assays on olfactory bulb of the mice. Further work was focused on understanding the mechanisms of trans-nasal delivery.

Impact:  

There are currently no effective treatments for GM1 gangliosidosis patients and Central Nervous System (CNS) delivery remains the fundamental barrier to Enzyme Replacement Therapy (ERT) strategies for these patients. There are different drug delivery routes available. Transnasal delivery, with its distinctive advantage of being convenient and non-invasive, offers potential of treating brain disorders like GM1. This research tested a lectin-based ERT carrier that may facilitate transnasal delivery of corrective β-gal to the brain in the GM1 mouse model. The results from this study will lay a foundation for further work on the intranasal enzyme therapy delivery for patients with GM1 and other neurodegenerative diseases.

 

Our families' daily struggles drive us to extend our leadership in and financial support of the research that will ultimately lead to a cure. Now more than ever, the potential exists to advance science toward effective treatments.

Funding Innovative Research

NTSAD launched its Research Initiative in 2002 to focus on funding promising innovative research for neurodegenerative diseases that affect the central nervous system. We fund promising research that may lead to major grant support and programs that will hopefully lead to clinical trials. 

Collaboration

NTSAD's grants are sometimes made in collaboration with partners such as the NIH and other patient advocacy groups for the allied diseases.

These grants went on to receive over $10 million in funding through NIH!

Advanced Research

The Tay-Sachs Gene Therapy Consortium is the most advanced research program and holds tremendous potential as they get closer to initiating a human clinical trial.

We can only fund research with the generous financial support of our families, affiliates and chapters. We encourage you to support this research by making a gift.

Past Grants

Read about the braod array of research grants NTSAD has funded.

2016 Research Initiative Grants

2015 Research Initiative Grants

2014 Research Initiative Grant

2012-2013 Research Initiative Grants

2011 Research Initiative Grants

2010 Research Initiative Grants

2009-2002 Grants


Alessandra d’Azzo, PhD
St. Jude Children's Research Hospital

Studies of the Molecular and Biochemical Bases
of Neurodegeneration in Sialidosis

Description:

Scientists from d’Azzo Lab analyzed the effects of NEU1 deficiency in the sialidosis animal model. A set of genes were also identified and studied, as their expression patterns were affected by the loss the enzyme NEU1 and were therefore likely contributors to disease pathogenesis.

Impact:

Neuraminidase 1 (NEU1) is the key lysosomal enzyme in brain cells that normally are used to digest and either recycle or dispose of glycoproteins. The patients of sialidosis, a rare pediatric lysosomal storage disease, have too little or no enzyme and present with pathologic features that scientists have successfully reproduced in an animal model of the disease.

Researchers at d’Azzo Lab have extensively used the laboratory animals to study mechanisms of pathogenesis linked to NEU1 deficiency. It was previously discovered that NEU1 deficient animals have alterations in the brain that resemble Alzheimer’s disease (AD), a neurodegenerative condition that usually develop in older adults [1]. The finding triggered a hypothesis that NEU1 may represent a risk factor of AD conditions, and could potentially be exploited not only for the treatment of sialidosis but also as a novel therapeutic target for AD.

The current work aimed to further analyze the molecular and biochemical events downstream of NEU1 deficiency. The resulting newly identified genes and their products could potentially be used for diagnostic and therapeutic purposes for both sialidosis and AD patients. The results from this study were published in the journal of Nature Communication 2013 [2].

Link of resulting publication in PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/24225533

[1] Zanoteli, E., van de Vlekkert, D., Bonten, E. J., Hu, H., Mann, L., Gomero, E. M., Harris, A. J., Ghersi, G., and d'Azzo, A. Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue, Biochim Biophys Acta 2010, 1802, 659-672.

[2] Annunziata I., Patterson A., Helton D., Hu H., Moshiach S., Gomero E., Nixon R. & d’Azzo A. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-b secretion via deregulated lysosomal exocytosis. Nature Comm. 2013, 4, 3734.

 

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