Tay Sachs Disease (TSD) is a rare hereditary disease that is transmitted when an individual inherits two copies of autosomal chromosomes with a gene for the disease. The pathophysiology of the disease involves accumulation of GM2 ganglioside in the lysosome of nerve cells of the CNS as a result of a deficiency of β-hexosaminidase A which an enzyme that is responsible for degrading GM2 ganglioside (Solovyeva et al., 2018). The accumulation of GM2 ganglioside results in destruction of neurons, proliferation of microglia, inflammatory changes within the brain all which culminate in neurodegeneration.
The disease mainly starts at infancy and is characterized by loss of muscle power as the baby grows and this is associated with loss of motor functions for example sitting, standing, crawling. As the child grows, the progress of the disease worsens and the baby develops convulsions, ability to hear and see deceases sometimes progressing to full blown disease where they lose their vision and their hearing ability (Solovyeva et al., 2018) . Further, the intellectual capacity of the baby declines coupled with paralysis and this culminates in the death of the baby at a very tender age because of the wide range of complications. The disease is common among the Ashkenazic Jews, French Canadian and Cajun populations. Although the juvenile form of the disease is the most common, the disease can also develop later in life although these forms of disease are mild in nature. Symptoms of these late onset disease include; muscle weakness, speech problems, ataxia and mental illnesses.
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The recent developments in technology especially the development of gene therapy has sparked interest in this area with many researcher engaging in research on how this disease can this disease can be managed definitively because currently only symptomatic treatment of the disease is available. Current treatment modalities include substrate reduction, neural stem cell transplantation, use of anti-inflammatory medication, gene therapy, bone marrow transplantation.
Substrate reduction Therapy
This form of therapy aims at reducing the rate of deposition of the offensive ganglioside by way of reducing the rate of glycolipid biosynthesis. A molecule that has been applied successfully in this form of therapy is miglustat which has been shown to reduce the rate of deposition of ganglioside by 50% in experiments involving mice. This molecule is a competitive inhibitor of glucosylceramide synthase which is an enzyme that catalyzes the first committed step leading to the glycosphingolipid synthesis (Solovyeva et al., 2018). The advantage of this molecule is that it possesses the capacity to penetrate the blood brain barrier to exert its effects in the CNS. This is demonstrated by finding of the molecule in the CSF fluid. The use of this therapy in patients with TSD has not shown any benefit with regards to stopping the progression of neurological symptoms but has however been recommended in the prevention of macrocephaly which could stem of accumulation of gangliosides in the neurons.
Enzyme Replacement Therapy
This form of therapy involves replacing the deficient enzyme which results in the development of the disease by accumulation of GM2 ganglioside. So far, research has found that ERT helps in improvement of somatic symptoms but unfortunately, the drug has no benefit in preventing brain neurodegeneration because the drug does not permeate the blood brain barrier (Solovyeva et al., 2018) .
Pluripotent Stem Cell Transplantation
In this treatment modality, pluripotent stem cells from a healthy patient without the defective genes are transplanted to the brain whereby they differentiate into neurons. Since the new generation of neurons are normal, their population helps to replace the damaged neurons and this helps in relief of symptoms (Cheung, 2016). It is important that the donors and the recipient’s HLA antigens match to a transplantation reaction. In most cases requiring stem cell replacement therapy, umbilical cord blood acts as a very important source of the progenitor cells. Alternatively, blood marrow can also be used as a source of the pluripotent stem cells. In vivo studies involving pluripotent cells transplant in mice showed that bone marrow transplant was able to prolong the lifespan of the mice for 3 months and also helped to improve the neurological symptoms of the animals (Solovyeva et al., 2018) . There is also a case documented where bone marrow therapy was used simultaneously with substrate reduction therapy and there was an increase in HexA activity in leukocytes but unfortunately there was no benefit shown in terms of preventing neurological dysfunction (Solovyeva et al., 2018) . All in all, use of umbilical cord stem cells transplantation is a promising therapy for the management of the condition and further research needs to be conducted into this area.
Gene Therapy
This form of therapy aims at replacing the defective gene with a normal gene. Replacing the defective gene with the normal gene would restore the normal functioning of the affected parts of the brain and this would reduce deposition of GM2 ganglioside thereby improving the symptoms of the disease. Transfer of the normal gene to replace the defective gene is carried out by using a vector (Cachon-Gonzalez et al., 2018). In most cases of gene therapy, adeno viruses have been used as the vectors of delivering the gene (Whitley, 2009). In vivo experiments involving mice whereby intravenous administration of a vector carrying HEXA and HEXB transduced the liver instead of the CNS cells. This led to secretion of the deficient enzyme into the serum instead of the CNS where it mainly acts. The main challenge encountered in this approach is the fact that the vector carrying normal genes do not cross the blood brain barrier which hinders the transfer of the genes to the part of the CNS where they are needed most. Additionally, the vector has a huge affinity for liver cells. The development of a transgene puts the patient at an increased risk of developing hepatocellular carcinoma (Solovyeva et al., 2018) . Therefore, the main challenge encountered in gene therapy is the choice of vector to deliver the gene and the mode of delivery of the vector to the parts of the brain that are affected. More research is needed into this area and once these obstacles are overcome, gene therapy promises to be the most effective treatment modality for this disease.
Genetically modified multipotent cells
Considering the many challenges encountered in using gene therapy in terms of lack of an appropriate vector and lack of appropriate mode of delivering the vector due to the blood brain barrier, transfer of genetically modified multipotent neural cells is a very promising strategy. Over the years, researchers have been able to develop Multipotent neural cells with human HEXA gene overexpression a process that is achieved by retroviral transduction. These cells demonstrated the ability to secrete the deficient enzyme in TSD. When the cells were injected intracranially to mice, they showed significant human HexA subunit transcript and this resulted in secretion of significant amounts of the deficient enzyme (Solovyeva et al., 2018). Even though this research has only been conducted in mice, it shows high promise if the same can be repeated with humans.
In summary, TSD can be managed by use of various approaches which aim to restore the deficient enzyme that results in accumulation of GM2 ganglioside in the neurons which results in neurodegenerative changes in the affected parts of the brain. Some of the approaches that have shown promise include substrate replacement therapy, Enzyme replacement therapy, bone marrow transplant, gene therapy, transplant of genetically modified pluripotent stem cells. Each of these methods have their shortcomings and more research should be devoted to the most promising methods to ensure that a definitive treatment for this disease is acquired.
References
Cachon-Gonzalez, M., Zaccariotto, E., & Cox, T. (2018). Genetics and Therapies for GM2 Gangliosidosis. Current Gene Therapy , 18 (2), 68-89. https://doi.org/10.2174/1566523218666180404162622
Cheung, M. (2016). Neural Crest Stem Cells/Progenitors and Their Potential Applications in Disease Therapies. Journal Of Stem Cell Research & Therapeutics , 1 (2). https://doi.org/10.15406/jsrt.2016.01.00014
Solovyeva, V., Shaimardanova, A., Chulpanova, D., Kitaeva, K., Chakrabarti, L., & Rizvanov, A. (2018). New Approaches to Tay-Sachs Disease Therapy. Frontiers In Physiology , 9 . https://doi.org/10.3389/fphys.2018.01663
Whitley, C. (2009). 151. Gene therapy for Tay-Sachs disease. Molecular Genetics And Metabolism , 96 (2), S45-S46. https://doi.org/10.1016/j.ymgme.2008.11.152
