Enzyme Replacement Therapy For Tay-Sachs Disease

Overview

Tay-Sachs disease is a fatal disorder that leads to neurodegeneration. It is a rare disease (an estimated 5,000 cases in the United States) that is heritable from parents that carry a mutated gene and is often diagnosed in infants, although there have been cases of late-onset Tay-Sachs disease in adults. According to the National Organisation of Rare Diseases (NORD), certain ethnic groups are more susceptible to the disease including those of Ashkenazi, Cajun (in South Louisiana, USA), and French Canadian (South Eastern Quebec) descent. There is no current cure for Tay-Sachs disease, but ongoing clinical trials are aiming to treat the disease, one of which includes Enzyme Replacement Therapy (ERT).¹

What is tay-sachs disease?

A brief overview of genetics

DNA, or deoxyribose nucleic acid, is the genetic information that is the building blocks of an organism.² This genetic information, or genes, are packaged into chromosomes. In humans, there are a total of 23 paired chromosomes. 22 of these chromosomes are called “autosomal chromosomes” while the 23^rd chromosome pair is dubbed the sex chromosome. When an individual is born, that individual receives two copies of a gene (one from each parent; one of each autosomal chromosome).³ Mutations in these genes can either be dominant or recessive; if a mutation is dominant, only one copy of the gene is necessary to cause disease. If a mutation is recessive, two copies are needed for the mutation to cause disease.³ 

The genetics of tay-sachs disease

Tay-Sachs disease is an autosomal recessive disease, and therefore, an individual requires two copies of the mutated gene to cause symptoms.¹ As an example, let us define T as equal to a functioning gene, while t is equal to a dysfunctional gene (where T or t is a haplotype). As humans generally have two copies of a gene (genotype), a healthy individual will have the genotype TT, a carrier of the disease will have the genotype Tt, and a diseased individual will have the genotype tt. The following charts, also known as Punnett squares, show the probability of inheritance of Tay-Sachs disease out of four children. 

Table 1. Healthy Offspring (No carrier parents): All offspring (4/4) are healthy (100%).

Table 2. One Parent is Carrying the Disease: All offspring will present as healthy, but two (50%) of the offspring will be carriers of the disease, these offspring will not show indications of disease, and will only be identified if screened.

Table 3. Both Parents are Carrying the Disease: Three of the offspring will present as healthy, however two (50%) of the offspring will be carriers. One of the offspring (25%) will have the disease, in this case, Tay-Sachs disease.

A summary of the probability of inheritance is simplified in the table below:

Due to the probabilities above, the NHS notes the importance for those who may be at higher risk of carrying Tay-Sachs disease to carry out a genetic test or screening before planning a pregnancy with their significant other. 

The biology of tay-sachs disease

Genes are responsible for the code that forms proteins and proteins are essential for reactions to take place in the body.² Therefore mutations in genes can lead to either dysfunctional proteins or lack of their formation causing serious detrimental effects. In individuals with Tay-Sachs disease, the gene, HEXA, is mutated, leading to reduced or absent effects of the beta (β) hexosaminidase A protein (β-HexA enzyme).^1,4 

Enzymes are proteins with specific functions, and in the case of the β-HexA enzyme, are responsible for the breakdown of fats (or lipids) known as gangliosides, specifically the GM2-type ganglioside.² Gangliosides are necessary lipids, and GM2 gangliosides are particularly prevalent in the central nervous system (CNS), meaning our brain, spinal cord, and neurons.^1,4,5 They play significant roles in the cell membrane of neurons and are involved in regulating the activity of peripheral membrane proteins and cell communication.⁶ 

Tay-Sachs disease is classified as a type of GM2-gangliosidosis and is biologically a lysosomal storage disease.¹ Lysosomes are responsible for the breakdown of both fats and carbohydrates, and when there is an accumulation of GM2 gangliosides, the lysosome is unable to function leading to the degeneration of cells in the CNS, thus causing inflammatory effects to surrounding cells (cytotoxicity) and eventual cell death.¹ 

Types of tay-sachs disease: signs and symptoms

There are three known forms of Tay-Sachs disease:⁴

Enzyme replacement therapy

What is enzyme replacement therapy?

Given that lysosomal diseases lead to the inefficient production of a specific enzyme’s activity, researchers have looked into whether these enzymes could be injected back into the body, i.e. enzyme replacement therapy (ERT). This was first tested for patients with Gaucher disease by a team of scientists led by Roscoe Brady.⁸ Over decades, Brady et al. created a method by which enzymes could be delivered to the lysosome. This was achieved by exploiting the human immune system. When unknown material enters the body, the first line of defence employed by the immune system generally includes the use of macrophages, a type of white blood cell.⁹ 

Macrophages have multiple receptors (macromolecules that bind to a specific object) that bind to various structures, including sugars.¹⁰ One specific receptor is the CD206 receptor, which is responsible for recognising mannose on proteins.¹¹ By engineering sugar residues (mannose) onto the enzyme, macrophages can deliver the ERT into the lysosome via the endocytic pathway (a pathway responsible for internalising external material) and therefore break down the accumulated toxic build-up.^8,12 Regarding lysosomal diseases, ERT has been approved for Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis type I, type II, and type VI.

Can enzyme replacement therapy be used for tay-sachs disease?

Unfortunately, ERT has not shown to be a sustainable treatment for Tay-Sachs disease. This is due to the nature of the disease, as well as the nature of the HexA enzyme. The HexA enzyme is composed of two subunits, an alpha (α) and beta (β) subunit.¹³ This can be challenging, as the assembly of the subunits to form the enzyme is a significantly dynamic process. As proteins and enzymes change structures (i.e. fold) to activate, it is a technically challenging and costly process to design two subunits that interact correctly and efficiently comparably to a healthy individual's HexA enzyme.¹⁴ Injection of these enzymes have been trialled, and have shown to decrease symptoms, but are unable to break down the lipids in the brain.^4,13 This is due to the blood-brain barrier (BBB), as the BBB is tightly packed and selective in what molecules can pass.^4,13,15

Current treatments for tay-sachs disease

According to the NHS, treatments for Tay-Sachs disease are generally aimed at improving quality of life, including:

• Seizure medicine
• Stiffness medicine
• Speech and language therapy
• Feeding tubes
• Physiotherapy
• Antibiotics (if infection occurs)

Other ongoing clinical trials

Gene therapy is the process of delivering material directly into the cells aiming to directly correct the mutated gene.¹⁶ This includes delivery of the corrected gene into a vector that is then injected, aiming to reach specific cells. These vectors can include lipid vectors and viral vectors. Viral vectors are said to be more efficient due to their ability to integrate indefinitely into the genome, but they do not carry a lot of genetic information (leading to needing more injections, which can be costly), and can additionally cause other issues such as immunogenesis.¹⁶ Nevertheless, clinical trials in mice have shown higher survivability, fewer symptoms, and less presence of unwanted GM2 lipids in the brain.¹⁷ This, however, has not been tested yet in humans. 

FAQ's

How long would ERT take?

ERT is a lifelong treatment, and administration can take up to four hours. Since it does not cure the presence of unwanted GM2 lipids in the brain, ERT is not the most sustainable treatment option. 

What are the side effects of ERT?

In clinical trials, the most frequent symptoms were chills, flushing, headache, fevers, nausea, vomiting, and abdominal pain.

Summary

Tay-Sachs disease is a rare lysosomal disease caused by the mutation of the HEXA gene. It leads to the accumulation of lipids known as GM2-type gangliosides and eventually leads to neurodegeneration. It is an autosomal recessive disorder, meaning that if both parents are carriers of the disease, there is a 25% chance that a child born from these parents will have Tay-Sachs. Tay-Sachs is predominantly diagnosed in children and usually leads to fatality, however, late onset of Tay-Sachs disease in adults is also possible. Enzyme Replacement Therapy (ERT) is effective in some lysosomal diseases but is not a sustainable treatment for those with Tay-Sachs disease. There are ongoing clinical trials of other treatment options which show promising results but have yet to be tested on human patients.