GM2 Gangliosidosis (Sandhoff and Tay-Sachs) Research Overview
Sandhoff is a lysosomal storage disorder. It is caused by a mutation in the gene responsible for the vital enzymes called beta hexaminidase A and B). The role of these enzymes is to degrade a fatty substance or lipid called GM-2 ganglioside. In the absence of the enzymes, GM-2 accumulates abnormally in cells, especially in the nerve cells, or neurons, of the brain. This ongoing accumulation, or "storage", of GM-2 causes progressive damage and eventually death of the cells.
Tay-Sachs is a lysosomal storage disorder. It is caused by a mutation in the gene responsible for the vital enzymes called beta hexaminidase A (Hex-A). The role of Hex-A is to degrade a fatty substance or lipid called GM-2 ganglioside. In the absence of the enzymes, GM-2 accumulates abnormally in cells, especially in the nerve cells, or neurons, of the brain. This ongoing accumulation, or "storage", of GM-2 causes progressive damage and eventually death of the cells.
For more information, see All About Lysosomal Storage Disorders
Tay Sachs research is usually performed simultaneously with Sandhoff disease research. This is because these two diseases have a similar underlying biochemical mechanism.
N-Acetyl-L-Leucine for GM2 Gangliosidosis
Clinical Trial #NCT03759665
Queen's University (Taysha) - (recruiting)
First-in-Human Study of TSHA-101 Gene Therapy for Treatment of Infantile Onset GM2 Gangliosidosis
Clinical Trial #NCT04798235
Sanofi Genzyme (recruiting)
A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2 (AMETHIST)
Clinical Trial #NCT04221451
Sio Gene Therapies (recruiting)
The AXO-GM2-001 study is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of a bilateral thalamic and intracisternal/intrathecal infusion of AXO-AAV-GM2 in pediatric participants with GM2 Gangliosidosis (also known as Tay-Sachs or Sandhoff Diseases).
Clinical Trial #NCT04669535
Natural History Studies
Natural History Study for Pediatric Patients with Early Onset of either GM1 Gangliosidosis, GM2 Gangliosidosis, or Gaucher Disease Type II
Clinical Trial #NCT04470713
Patient with either GM1 gangliosidosis, GM2 gangliosidoses (Tay-Sachs, Sandhoff, or AB Variant), or Gaucher Disease Type 2.
Diagnosis confirmed by either biochemical (enzyme activity) or genetic testing, or both.
Date of birth on or after 1 January 2000.
Onset of first neurological symptom within 24 months of age.
Informed consent of parent or legal guardian as required by local law.
Substrate Reduction Therapy
Several substrate reduction therapies have delayed symptoms and prolonged survival in Tay-Sachs and Sandhoff mouse models but this success has not always successfully translated into the same results with humans.
Substrate Reduction Therapy: Zavesca® (miglustat)
A clinical trial to evaluate the safety and efficacy of SRT using a drug called migulstat (brand name Zavesca) has also been conducted for late onset Tay-Sachs. Miglustat did not result in any measurable clinical benefit in the 20 late onset patients given 200 mg orally three times a day when compared to patients that did not take miglustat. Prominent side effects of the drug were weight loss and diarrhea, as this drug also effects the ability to digest complex carbohydrates. It remains unclear whether earlier treatment in more mildly affected patients would result in benefit. There are reports of benefits to individual patients with Tay-Sachs disease treated with miglustat, and further studies are warranted if coupled with detailed natural history studies to allow better interpretation of the outcomes of the trial.
The NTSAD Scientific Advisory Committee (SAC) subcommittee on experimental therapies recently reviewed the data regarding miglustat’s 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
Newborn Screening Investigation
Development and Validation of an MS-MS Method for the Detection of Hexosaminidase Deficiency in Tay Sachs (2015 Grant)
When therapy becomes available for Tay Sachs and Sandhoff, discovering the diseases as early as possible will be essential. Newborn Screening is performed on a dried blood spot via a technique called “tandem mass spectrometry,” which is used to detect reduced enzyme levels in these blood spots. There have been previous studies where the detection of reduced hexosaminidase activity was developed for Sandhoff Disease. This study aims to determine reference and cut off ranges for Tay Sachs Disease and will then pilot the test in Quebec.
To learn more visit 2015 Research Initiative Grants
Bone Marrow Transplant
Currently there are two centers in the United States that will consider Tay-Sachs, Sandhoff and GM1 patients for Bone Marrow Transplant - Duke University Medical Center and University of Minnesota. The Duke program is not an approved clinical trial.
Psychotropic Medications- Late Onset Tay Sachs
A study was done in 2006 where the researchers analyzed patients with LOTS who had taken certain psychotropic medications. They found that these medications worsened the neurological effects of LOTS. Read the full research publication Late-onset Tay–Sachs disease: Adverse effects of medications and implications for treatment.