Sandhoff Disease 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.
For more information, see All About Lysosomal Storage Disorders
Sandhoff Disease research is usually performed simultaneously with Tay Sachs disease research. This is because these two diseases have a similar underlying biochemical mechanism.
For information on participating in a study, please visit Studies Recruiting Patients.
Where are we with Sandhoff Research?
Gene Therapy Consortium for Sandhoff and Tay-Sachs
The Tay-Sachs Gene Therapy (TSGT) Consortium seeks rapid development of the most effective gene therapy approach for the clinical trial. To accomplish this goal, scientists and clinicians are pooling their resources and extensive experience in experimental gene therapy to devise the most effective adeno-associated virus (AAV)-based gene therapy approach for treating Tay-Sachs and Sandhoff disease.
Animal models have been created and vectors have been manufactured and tested. Learn more about Tay-Sachs Gene Therapy Consortium
Gene therapy Investigation in felines
Intravascular gene therapy for feline GM2 gangliosidosis (2015 Grant)
Aims to optimize IV gene therapy to treat the manifestations of Sandhoff Disease in both the central nervous system, and the rest of the body. Learn more at NTSAD Research Projects - 2015 Funded Research.
Gene Therapy Investigation- late onset Sandhoff
Generation of a knock in mutant HexB mouse model (2015 Grant)
Aims to create a mouse model which contains a specific mutation in the HexB gene. This mutation leads to a reduced amount of enzyme, as seen in late onset Tay Sachs or Sandhoff Disease. When this is accomplished, this mouse model will then be able to be used in later studies for studying the efficacy of chaperones which are being developed for LOTS/LOSD. Learn more at NTSAD Research Projects - 2015 Funded Research.
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
Molecular Chaperone Therapy- Late onset Tay Sachs
A 2009 Research Initiative grant from NTSAD was administered to Dr. Joe Clarke to support an open-label Phase I/II clinical trial of pyrimethamine, a pharmacological chaperone, for the treatment of patients affected with late onset Tay-Sachs or Sandhoff disease. This clinical trial evaluated the tolerability of pyrimethamine by patients, as well as the effectiveness of the molecule in raising Hex A levels in blood in a small number of patients. The study found that Hex A level was increased up to 4-fold in people taking 50 mg or less of the medication each day. When the dose was increased to 75 mg per day or higher, most participants had significant side effects, including worsening problems with coordination.
A pilot study (conducted prior to the above research) found that, although Hex A levels rose in patients, there was significant beneficial neurological or psychiatric effects.
Read the full research report as published in the Orphanet Journal of Rare Diseases, Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study
Bone Marrow Transplant
Stem Cell Therapy
Many potential treatments are currently being tested in animal models and some have already been brought to clinical trials for spinal cord injuries and diseases related to the eye (from http://stemcells.nih.gov/info/health.asp). Breakthrough work has been done in the Sandhoff mouse model and was partially funded by the NTSAD 2010 Research Initiative Grants, Lee and Snyder.
To learn more, read the research publication Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease, published by Nature Medicine, 2007.