As there is currently no successful treatment for individuals with Tay-Sachs disease, there is a need for significant research into therapeutic techniques that could be useful in the treatment for the disease.
Among the most promising research at this point in time are enzyme replacement therapy (ERT), the Jacob sheep model, substrate reduction therapy, and increasing the activity of β-hexosaminidase A.
What is Tay-Sachs Disease? (GM2 Gangliosidosis)
ERT has been considered as an approach for the treatment of Tay-Sachs disease and other lysosomal storage disorders.
The aim of ERT is to provide a replacement of the HEXA enzyme that can play the role of the non-functional enzyme of individuals with the disease. However, this process is limited by the physical size of the enzyme, which appears to be too large to traverse the blood-brain barrier (BBB) as necessary.
Some research has investigated the possibility of administering the HEXA enzyme directly into the cerebrospinal fluid (CSF) to surpass this issue. However, current research has not been able to show the successful uptake of the enzyme, even when it is administered directly to the central nervous system (CNS).
To date, this research approach has been futile; however, current researchers continue to examine the mechanism and consider administration techniques of the enzyme that could be effective.
Jacob Sheep Model
A rare breed of sheep, known as Jacob sheep, has been used as a model in the research of Tay-Sachs disease due to their susceptibility to the disease. The pathophysiology and the specific gene mutation of the disease are virtually identical in humans and these sheep, which advocates for the use of these animals as a research model.
Of particular note, research has discovered a certain mutation in the HEXA complimentary deoxyribonucleic acid (cDNA) of sheep with Tay-Sachs disease, known as G444R, which is a missense mutation. This arises due to a change of nucleotide at exon 11, leading to the splicing of the exon before it can be transcribed.
Although this finding has yet to provide a treatment for Tay-Sachs disease, it is a promising lead that is being investigated further in gene therapy clinical trials that may expand future treatment options.
Substrate reduction therapy
Substrate reduction therapy is a technique that involves the use of enzymes to increase the catabolism of the GM2 gangliosides in the CNS and thus substitute the role of the missing HEXA enzyme. The aim of this treatment approach is to prevent the accumulation of lipids, as well as the development of symptoms and progression of the disease.
Sialidase is one enzyme that has been considered in this therapeutic approach, as it enables the bypass of the genetic defect and the healthy metabolism of GM2 gangliosides to occur. Although this could be a promising treatment for Tay-Sachs disease, it has yet to be developed into a pharmacological form that is safe and effective.
Miglustat is also being investigated as a possible treatment, which works with an antagonistic effect on the glucosylceramide synthase enzyme. This enzyme is important in the synthesis of GM2 gangliosides and could, therefore, help in the treatment of the disease.
β-hexosaminidase A activity
Another approach that has been studied for the treatment of Tay-Sachs disease has been to increase the activity of the HEXA enzyme so that the deficiency that characterizes this disease is less significant.
This is primarily considered an option for late onset Tay-Sachs disease; however, patients with infantile Tay-Sachs disease tend to lack the enzyme completely and would not benefit from an increase in the spectrum of activity.
Pyrimethamine is a drug that has shown some activity in this area. Unfortuantely, the overall efficacy of this drug is not high, as the activity of β-hexosaminidase A is still much lower than in unaffected populations.