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Tay-Sachs, Canavan, GM1 and Sandhoff diseases

GM1 Research

GM1 Research Overview

GM1 is a lysosomal storage disorder. It is caused by a mutation in the gene responsible for a vital enzyme called betagalactosidase (β-gal). The role of β-gal is to degrade a fatty substance or lipid called GM1 ganglioside. In the absence of β-gal, GM-1 accumulates abnormally in cells, especially in the nerve cells, or neurons, of the brain. This ongoing accumulation, or "storage", of GM-1 causes progressive damage and eventually death of the cells.

For more information see All about Lysosomal Storage Disorders.

For information on participating in a study, please visit Studies Recruiting Patients.

What is the latest with GM-1 Research?

Gene Therapy Update

Gene therapy research is being conducted at Auburn University by Doug Martin, PhD.

This research is being conducted in a colony of cats which have GM1. These cats were treated by using an AAV virus as the delivery mechanism for the correct genetic information. The results of this research are promising and have led to Doug Martin and his team to file a pre-Investigational New Drug application with the FDA. The hope is that clinical trials can be launched at some point in 2019. In addition to significant NIH funding in 2010, the program has received support from the Cure GM1 Foundation and NTSAD.

2018 NTSAD Research Initiative Grants

Two of the three grants awarded this year are focused on GM1 research.

Role of Plasma membrane-ER Contact Sites in
GM1-mediated Neuronal Cell Death
Principal Investigator: Alessandra D'Azzo, PhD
St. Jude's Children's Research Hospital

GM1-gangliosidosis is a neurodegenerative lysosomal storage disorder that presents with a spectrum of severity. It is caused by genetic mutations in the B-Gal gene that affect the expression and/or function of the B-Gal enzyme, leading to impaired degradation of one of its major target substrates, GM1-ganglioside (GM1). GM1 is particularly abundant in the nervous system, because it is a major component of neuronal outer membranes. Thus, the direct consequence of B-Gal deficiency is the relentless and progressive accumulation of GM1 in lysosomes and other subcellular membranes, which leads to the death of neurons, neuroinflammation and neurodegeneration. A deep understanding of the cellular and molecular events downstream of B-Gal loss of function and GM1 accumulation may give us the chance to identify alternative ways to tackle the disease therapeutically or provide us with appropriate end points to assess the extent of functional reversal of phenotypic abnormalities after treatment.

With these studies we plan to evaluate in the mouse model of GM1-gangliosidosis how GM1 accumulation affects the membrane contact sites formed between cellular components and the neuronal outer membranes. In particular, we will analyze the protein and lipid components of these membrane contact sites in order to assess whether they are altered by abnormal local concentrations of calcium ions caused by the accumulated GM1. This will help us to understand the role of calcium and calcium-binding proteins at these contact sites in causing the damage to neurons. We will perform therapeutic proof of principle studies aimed to inhibit the function of a specific calcium-binding protein, which, if successful, may set the foundation for a novel therapeutic approach for the treatment of this lysosomal disease in children.

Oligosaccharide Biomarkers for Disease Progression and AAV Therapeutic Efficacy in GM1 Gangliosidosis
Principal Investigator: Xuntian Jiang,PhD
Washington University School of Medicine (St. Louis, MO)

A major challenge for developing treatments for GM1 gangliosidosis (GM1) disease is difficulty in evaluation of efficacy. This is complicated by limited patient numbers, and variability in age, severity, and stage of disease progression. Biomarkers that reflect disease status could provide a valuable surrogate endpoint for assessment of treatment effect and reasonably predict clinical benefit. We have identified an oligosaccharide (carbohydrate whose molecule is composed of a relatively small number of monosaccharides) biomarker that is significantly elevated in the urine, cerebrospinal fluid (CSF) and plasma from GM1 patients and brains from GM1 cat model. This biomarker in GM1 cat brains was reduced in response to gene therapy. These results suggest that the oligosaccharide is a sensitive biomarker for disease severity and progression and for assessing treatment efficacy. In this proposal, we will identify the structure of the oligosaccharide biomarker and evaluate this marker as a surrogate outcome measure of treatment for GM1. This project will provide a much-needed tool for assessing GM1 disease severity and therapeutic efficacy.

Enzyme Replacement Therapy

Lectin-assisted transnasal delivery of corrective enzyme for GM1 gangliosidosis research investigated by David Radin, PhD, Carole Cramer, PhD, and Alessandra d'Azzo, PhD – NTSAD funded project.

This study was done in mice with GM1. They investigated a mechanism where the β-gal enzyme can be delivered via the nasal passages, so the enzyme can be transported the brain. NTSAD received their final report and they concluded that β-gal:RTB successfully crosses the [blood brain barrer] to mediate significant positive impact on the GM1 disease substrate levels in the CNS (central nervous system). These impacts were seen broadly across the CNS including regions linked with GM1 pathologies. Future plans include studies to assess impacts of β-gal:RTB treatment at younger ages, to directly analyze impacts of treatment on cellular pathology and inflammation within brains of treated animals by imaging technologies, and to expand cohort sizes, β-gal:RTB dosage and frequency and treatment duration, and other preclinical studies needed to move these discoveries to clinical application.

Two journal articles describing the β-gal:RTB product and a new high-content image-based assay to quantitate GM1 disease correction at the cellular level were published in Molecular Genetics and Metabolism and Data in Brief in 2016. Results of the initial mouse trials were reported via posters and talks at several national and international conferences including the NTSAD annual family conference.
• Condori, J., Acosta W, Ayala J, Katta V, Flory A, Martin R, Radin J, Cramer C, and Radin D. 2016. Enzyme replacement for GM1-gangliosidosis: Uptake, lysosomal activation, and cellular disease correction using a novel β-galactosidase:RTB lectin fusion. Mol. Genet. Metab. 117: 199-209.
• Acosta W, Martin R, Cramer C, Radin D. 2015. High-throughput imaging method for direct assessment of GM1 ganglioside levels in mammalian cells, Data in Brief 6:1016-1022 [DIB-D-15-00660].

In September 2017 we learned NTSAD’s $160,000 Research Grant to BioStrategies had been leveraged as BioStrategies has received a two year NIH SBIR* Phase II award for $2,438,483 and will focus on developing a therapeutic drug to treat GM-1 based on the company’s proprietary innovative technology for delivering enzyme drugs to the brain and other hard-to-treat organs. Good news for the GM1 community.

Substrate reduction therapy: Zavesca® (miglustat) 

Clinical trials in babies, children and adults with Tay-Sachs and Sandhoff of the substrate inhibitor Zavesca® (miglustat) did not show therapeutic benefit. Zavesca is FDA approved for Gaucher which provides families affected by other lysosomal diseases the option of using the drug for off-label use. The FDA did not approve Zavesca®  for Niemann-Pick Type C (NPC) but this use was approved in Europe and Canada. 

Zavesca may have a small therapeutic effect on children affected by Juvenile GM-1. Contact our Executive Director at This email address is being protected from spambots. You need JavaScript enabled to view it. or (800) 906-8723 to learn more

The NTSAD Scientific Advisory Committee (SAC) subcommittee on experimental therapies recently reviewed the data regarding miglustat’s (Zavesca) safety and potential efficacy. View report on Substrate Reduction Therapy.

Off Label use study for Migulstat- currently recruiting participants

Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G) at University of Minnesota - Clinical trial #NCT02030015

This study has IRB approval, but it is not technically a clinical trial so does not have FDA approval.

The investigators are investigating a combination therapy using miglustat and the ketogenic diet for infantile and juvenile patients with gangliosidoses. Miglustat is a drug which was originally approved to help treat mild to moderate type 1 Gaucher disease (another lysosomal storage disorder.) Miglustat is an example of substrate reduction therapy, as described above. A ketogenic diet is a “high-fat, adequate-protein, low-carbohydrate diet.” One study found that this method improved the outcome for one patient with Sandhoff Disease. Researchers are now hoping to investigate this therapy in patients with Sandhoff, Tay Sachs and GM-1.

To learn more, including how to be part of this study please visit Studies Recruiting Patients.

Also see the case study in the European Journal of Medical Genetics