Utilizing gene-editing and stem cell therapy to create a novel treatment plan for Tay-Sachs disease

Video Transcript (Clean verbatim)

100% of people who are diagnosed with Infantile Tay-Sachs disease pass away between the ages of 2 and 4. This is because Tay Sachs disease is a genetic disorder that is caused by a mutation on the HEXA gene. This causes our bodies to be unable to code for an enzyme called Beta-hexosaminidase A. This enzyme is the only one in our bodies that can break down a lipid called GM2. GM2 builds up within our nerve cells and eventually causes our neurons to degenerate. Neuron degeneration can lead to symptoms such as blindness, seizures and eventually leads to death. Tay Sachs disease is a recessive disorder, which means that genetic testing can be done in utero to see if an infant is a carrier for the disorder. My treatment plan proposes the use of gene editing and stem cell therapy to edit the section of mutated gene and prevent symptoms from developing, reducing fatality rates.

Tay-Sachs disease is a rare genetic disorder that is recessive, and is described by neurological issues due to the death of nerve cells (neurons) within the central nervous system (CNS), which includes the brain and the spinal cord (National Library of Medicine).

The most common form of Tay-Sachs disease is called Infantile Tay-Sachs disease, and affects people early on in their lives. Infants diagnosed with Tay-Sachs typically develop normally until they are three to six months old. During this time infants with Tay-Sachs experience their muscles weakening, and often fail to achieve normal milestones as their development begins to slow, and they often begin to lose previously gained skills like sitting, rolling and crawling. As the disease progresses, infants will experience seizures, involuntary twitches, beginning at ages of two, and struggle with difficulty swallowing, hearing loss, and intellectual disabilities as early as six months. This form of Tay-Sachs disease typically leads to early fatalities, usually between the ages of two and five (National Organization for Rare Diseases), and has a fatality rate of 100%.

This study aims to utilize a combination of previously conducted research for the treatment of Sickle Cell Anemia, and novel proposals on how to use CRISPR/Cas 9, and stem cell therapy to edit the affected HEXA gene of Tay Sachs patients. This would allow the gene to code for beta-hexosaminidase A enzyme and reduce the mortality rate of Infantile Tay-Sachs disease patients from 100% to 30%, and improve quality of life for all Tay-Sachs patients.

The basis of this project stemmed from the question, would using gene editing (CRISPR-Cas9) to edit the HEXA gene on chromosome 15 allow for more beta-hexominidase A enzymes to form and break down GM2 ganglioside in Tay-Sachs patients, improving quality of life?

Sites such as Google Scholar, National Library of Medicine, and Medline Plus were used to ensure that the data being explored was credible and current.

In the beginning stages of this project, research was conducted through medical journals to understand what Tay-Sachs disease is, and how it affects people who inherit it. Following these investigations into the minutiae of this disorder, clinical trials that used gene editing to treat Sickle Cell Anemia and Leukemia were considered and the techniques used were analyzed and inspired this treatment plan.

Throughout the research stages of this project, a correlation between Tay-Sachs disease and Sandhoff's disease was drawn, which lead to an additional hypothesis stating, if this treatment was applied to Sandhoff disease patients with the genetic editing being applied to both the HEXA and HEXB genes, then it could reduce the fatality rates for Sandhoff’s disease patients, by limiting build up of toxic lipids and preventing neuron degeneration.

This course of treatment was developed with current procedures that are already able to be performed such as, genetic testing in utero, and stem cell therapy, in mind. It also took into account novel technologies that are currently being tested such as, CRISPR/Cas9, and gene editing.

While this treatment plan is a theoretical proposal, it is based on relevant research that is current and up-to-date, while exploring new avenues for gene-editing on a genomic level working in tandem with stem cell therapy to create a novel medical protocol for the course of treatment for Tay-Sachs disease, and Sandhoff’s disease patients.

Through the development of this project, methods used to treat Sickle Cell Anemia were examined in order to uncover if similar technologies could be used to treat Tay-Sachs disease. It was discovered that Tay-Sachs disease is caused by a gene-mutation on the HEXA gene on chromosome 15, which causes an inability to code for the alpha subunit required to make the enzyme Beta-hexosaminidase A to break down GM2 ganglioside. This causes GM2 to build up in nerve cells, causing them to ultimately degenerate (Figure 1).

Due to the fact that Tay-Sachs disease is a recessive, genetic disorder, a patient with the disorder must inherit a mutation of the HEXA gene from both parental sets of DNA. The gene mutation can be a deletion, which causes a frameshift mutation to occur, shifting all nucleotides after the mutation forwards. It could also be a substitution, in which one base is switched with another, or an insertion, where an additional base is added. Figure 2 is a Sanger DNA sequencing chromatogen, and demonstrates how inheriting pathogenic mutations from both sets of parental DNA can result in a hereditary disorder. Panels A and B show an example of what DNA sequencing of the HEXA gene can look like for a Tay Sachs patient, and panels C and D show the mutations that were inherited from the parental DNA.  These mutations can cause a premature stop codon to be produced, inhibiting the HEXA gene from coding for the alpha subunit needed to create the enzyme, Beta-hexosaminidase A. This enzyme is the only one that can break down GM2 ganglioside, a toxic lipid which builds up in the neurons of Tay-Sachs disease patients, and causes them to degenerate.

In order to resolve this, it was proposed that CRISPR/Cas 9 technology be used to remove the defective section of the HEXA gene through stem cell therapy, and a healthy, functional section of the HEXA gene be introduced. It is believed that using this method would allow for the missing Beta-hexosaminidase A enzyme to be produced and delivered to nerve cells in the Central Nervous System and break down GM2 ganglioside.

After conducting further research, an additional hypothesis was proposed stating, if this novel treatment were applied to Sandhoff disease patients with the genetic editing being applied to both the HEXA and HEXB genes, then it could reduce the fatality rates for all Sandhoff’s disease patients, by limiting build up of toxic lipids and preventing neuron degeneration.

The current fatality rate for Infantile Tay-Sachs disease is 100%, and using the proposed treatment could reduce that to approximately 30%, with respect to success rates of stem cell therapies and diagnosis ages. If Tay-Sachs patients are diagnosed within the average ages of three to six months, this treatment could prevent the development of seizures, complete hearing loss, and other symptoms, as well as death. Further, if treatment is successful, it could be used to treat Sandhoff disease, which is caused by mutations similar to that of Tay-Sachs disease.

A treatment plan for Tay-Sachs disease was developed through the analysis of various medical journals and websites that address the causes of Tay-Sachs disease, uses of CRISPR/Cas 9, and stem cell therapies.

This care plan was established by proposing a stem cell therapy treatment which utilizes CRISPR/Cas9 to edit the HEXA gene on chromosome 15 to allow for it to code for the enzyme Beta-hexosaminidase A.

Using this treatment could reduce the fatality rate in Infantile Tay-Sachs patients from 100% to 30%, while also improving quality of life. While progressive loss of nerve cells cannot be reversed, further neuron death can be avoided with this treatment. This would prevent symptoms like hearing loss, seizures and intellectual disabilities from developing further, and reduce fatality rates.

After analysing all of the data collected, it is hypothesized that, if CRISPR/Cas9 was used to edit the HEXA gene on chromosome 15 to allow for beta-hexosaminidase A enzymes to form, then the degradation of neurons in Tay-Sachs patients would slow. Due to the build up of the lipid GM2 ganglioside being prevented this treatment plan would ultimately improve the quality of life for Tay-Sachs patients, and reduce fatality rate from 100% to 30%.

After conducting further research, an additional hypothesis was proposed suggesting that if a similar approach to the proposed treatment for Tay-Sachs disease patients was used to treat Sandhoff’s disease patients, it would yield results similar to those previously hypothesized for Tay-Sachs disease patients, such as reduced fatality rates.

Future steps for this project would entail getting the treatment plan peer-reviewed by professionals in this field.

Further modifications could be made to the course of treatment by testing the edits made to the genetic code in an online program, to verify that replacing the mutated sections would result in a healthy HEXA gene that could produce Beta-hexosaminidase A.

Following this testing, a model Tay Sachs DNA code could be created in a simulator. Using this online model, the stem cell therapy could be tested to demonstrate if this care plan could prevent symptoms from developing further, and prevent fatality.

Thank you to my biology teacher, Mrs. Lentz, for inspiring my interest in genomics and mutations, which motivated me to explore further developments which could be made in this field.

Thank you to Erik Couture for organizing our regional science fair, ensuring that it happened, and for assisting in all of the steps that followed.

Thank you to Hilary Evans, and the rest of the judges for supplying feedback to help the further development of this project.

Lastly, thank you to my family who supported me throughout the entire process of creating and developing this project.

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