Genetic Disorders and Gene Therapy

Genetic disorders have long plagued humanity, with 3.5%-5.9% of people suffering from a rare genetic condition. People with genetic disorders can experience disadvantages that can range from inconvenient to lethal.

One common and dangerous genetic disorder is sickle cell anemia. Sickle cell anemia is caused by abnormalities in the gene responsible for the production of hemoglobin, the compound in red blood cells that allows them to carry oxygen. Sickle cell anemia causes red blood cells to take on a crescent shape instead of the typical disk shape, which makes them unable to carry as much oxygen as normal cells. As a result, people with sickle cell anemia can experience pain, fatigue, and even death.

Recently, gene therapy has emerged as a possible method of battling genetic disorders. Gene therapy is the delivery of a gene to the body or the permanent alteration of the cell’s DNA with the purpose of treating disorders. Once this genetic material is transferred into or altered in the recipient’s cells, the mutated cells are able to produce different proteins. If a transfer of genetic material is made, this happens as the cell incorporates the material into the cell’s processes. If an edit of DNA was made, this happens as the new DNA gives different instructions to different parts of the cell, some of which are responsible for protein production. This change in protein products is what treats genetic disorders.

However, the delivery of foreign genes is difficult due to the body’s immune response. There are two methods of overcoming immunological barriers. The first is viral delivery. In 1980, biochemist and Professor at Stanford University Paul Berg discovered viral delivery, a method of gene delivery that repurposes viral capsid to deliver DNA material. The second method is nonviral delivery. It was first invented by Professor Philip Felgner and his colleagues in 1987 and involves the use of synthetic material to encapsulate the DNA. These capsids are called vectors. Even with these vectors, it is extremely difficult to get DNA past the cellular membrane because the body does not like to accept foreign genes, and it is still unknown whether there is an effective way to do so.

There are drawbacks and benefits to each type of delivery. Viral delivery is more effective and has a higher rate of successful gene delivery. The effects of viral delivery are also generally long lasting. However, since viral capsids are used, viral delivery is more likely to trigger an immune response compared to nonviral delivery.

On the other hand, nonviral delivery is not only less likely to trigger an immune response but also more affordable. Nonviral vectors are far cheaper to manufacture than viral vectors, creating potential for mass production. The major drawback of nonviral delivery is that the resulting gene expression is transient, necessitating repeated transfers which puts a greater physical strain on the recipient of the nonviral delivery.

In the context of sickle cell anemia, the FDA recently approved two gene therapies, Casgevy and Lyfgenia. Casgevy is a nonviral therapy that utilizes Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), a new gene editing technology. This modifies blood stem cells to produce more fetal hemoglobin (HbF), an oxygen-promoting hemoglobin which can reduce the side effects of the disease. On the other hand, Lyfgenia uses lentiviral vectors in viral delivery to make blood stem cells produce a special type of hemoglobin called HbAT87Q which reduces the risk of sickling. Both Casgevy and Lyfgenia involve the removal of a patient’s blood stem cells, modification of those cells, and then the reintegration of those cells back into the bone marrow.

While Casgevy and Lyfgenia have the potential to save and improve lives, they also have many drawbacks. The therapies can be draining, as they are year-long treatments. Since they both involve chemotherapy, which is very physically demanding, the therapies can result in side effects such as nausea, vomiting, sores, and abdominal pain. The type of chemotherapy used in the procedures can also lead to infertility. Lyfgenia treatments have also resulted in blood cancer on two separate occasions, deterring many people from using it out of fear of developing cancer themselves. Another important drawback is that treatment with either Casgevy and Lyfgenia for one person will cost approximately 2–3 million dollars. This is a price a vast majority of people cannot afford.

“The power to control our species’ genetic future is awesome and terrifying. Deciding how to handle it may be the biggest challenge we have ever faced,” wrote American Biochemist Jennifer Doudna.

It seems like gene therapy is currently at a tipping point. With more research and improvement on its safety and accessibility, it has the potential to become a revolutionary tool in medicine. However, since current risks outweigh the rewards, especially considering the financial burden that comes with procedures, it does not seem like gene therapy for genetic disorders will become practical on a large scale without major changes being made.