Gene Therapy as Treatment of The Future
Gene therapy is one of the treatments being developed to treat genetic disorders and other various diseases by modifying genes inside our cells. The treatment has some promising results. But safety is still a concern for patients, as indicated by early gene therapy that doesn’t have much information regarding the safety of viral vectors and immune system response which led to the death of patients within clinical trials. So what changes since 20 years ago led to the rise of gene therapy today?
Imagine the way you are living right now, breathing, eating, talking, and hearing perfectly, nothing seems wrong, and you just go to school or work every day just fine. However, this is not the case for people who have a genetic disorder. There are more than 7000 rare diseases with 25 and 30 million people affected in the United States alone.
Genetic disease is commonly caused by a mutation in human DNA which led to numerous living styles which limit a person’s capability every day. For example, you may be born without an immune system so you must live in a sterile environment. Maybe you have also heard of cystic fibrosis which is a genetic disorder that causes mucus to build up in the lung that led to breathing problems, infection, and shorter life expectancy. Because the source of the problem is inside our DNA it’s very hard to find an effective treatment. That’s where gene therapy comes in.
Gene therapy and the purpose behind it
Gene therapy is basically a treatment for gene improvement by modification of mutated genes inside our DNA into the correct form. If the defective gene sequence in our DNA is replaced by the correct sequence then our cell will start to produce the normal protein or enzyme instead of being dysfunctional.
Gene therapy commonly uses viruses as a vector (viral vectors) that have been inserted with recombinant DNA consisting of the correct sequence. The viral vector will be inserted into the extracted patient cell and the viral vector will release the recombinant DNA into the cell which will replace the defective gene in the patient cell. Then the modified patient cell will be transferred back into the patient.
However, gene therapy still needs more research to improve the efficiency and safety of the treatment, as seen in early clinical trials.
The First Death
In 1999, Jesse Gelsinger an 18-year-old suffered from a genetic disorder ornithine transcarbamylase deficiency (OTC). The genetic disorder caused ammonia to build up leading to a toxic amount in the blood which can lead to permanent damage to the brain and death. The body can’t produce a certain enzyme to convert excess nitrogen from protein into urea. So patients who inherited this genetic disorder must live under a strict non-protein diet and control their OTC well.
OTC genetic disorder is caused by a mutation within the gene. However, gene therapies are not well-developed at the time. Therefore, scientists must develop and study it first from laboratory and clinical trial results.
One of the clinical trials in 1999 by the University of Pennsylvania seek to cure OTC by using gene therapies. The therapy Jesse Gelsinger was involved in was using an engineered adenovirus to deliver the correct sequence of OTC genes to liver cells. At the time, adenovirus was considered to be safe for gene delivery. However, Jesse Gelsinger’s immune system responded strongly to the adenovirus. There was a severe inflammatory response followed by organ failure and in the end, brain damage occur which lead to his death after 4 days after treatment.
Jesse Gelsinger was the first person to die in a gene therapy clinical trial. His death will be remembered to this day as a reminder for scientists to develop a safe and effective gene therapy treatment. However, it was also to be noted that the investigation into Jesse Gelsinger’s case reveals that there are some past reports that the virus vector used for Jesse’s therapy actually makes some animals sick. This information is not communicated properly to Jesse Gelsinger and other volunteers so they believed that the risk was lower than the true risk.
What changed since then?
Now, gene therapy is achieving better result than they were 20 years ago. In some cases, patients who have developmental and motor disabilities start to walk and use muscles normally. But how?
- Change of a viral vector
Scientists are developing safer-to-use viral vectors such as an adeno-associated virus (AAV). This viral vector is different from adenovirus which is used 20 years ago for Jesse Gelsinger. AAV is a shell made from protein that surrounds a small viral DNA. For gene therapy scientist use a variant of AAV called recombinant adeno-associated virus (rAAV) which lack viral DNA so basically it’s just a shell made from protein that contains DNA with the correct sequence of the targeted gene. From clinical trials, it’s known that AAV has low immunogenicity meaning that the immune system will not react strongly like adenovirus so if combined with the absence of viral DNA in rAAV, this viral platform is very suited for gene therapy.
- Modification of viral vector enhancing the safety of treatment
One of the leading concerns about viral vectors in gene therapy is the ability to activate the cancer-causing gene. This was seen in the case of severe combined immunodeficiency syndrome (SCID) gene therapy developed by scientists in France and England using gammaretroviruses. People who inherited this disease lack an immune system, so they are in constant threat of deadly infections and must live using a sterile bubble environment. Initially, the therapy look successful. Patients consisting of 10 children start to produce one of the most important immune system components which is the T cell. However 3 to 6 years later, one of the patients die and half of the patients developed leukemia. It was believed that the main reason for this occurrence is due to the activation of a cancer-causing gene by the viral vector.
As a response to this, scientists modified the gammaretroviruses to avoid cancer-causing gene activation. As a result, in another clinical trial after nearly a decade, no one developed signs of leukemia or other side effects.
- More understanding of immune system response toward gene therapy
One of the greatest contributions to the safety of gene therapy is a better understanding of immune system response. One of the limitations in research is by using an animal model which allows scientists to understand the immune response to some degree but sometimes it can be very different when it’s being tested on humans. That’s why clinical trials are important, to understand the effect on humans and the efficiency of gene therapy.
This particular part of improving gene therapy safety is an accumulation of numerous clinical trial data over several years by many participants involved in clinical trials.
Future of gene therapy
As more clinical data is generated and more efficient and safe treatments are being developed, I think gene therapy will definitely become a way to cure diseases specifically caused by mutation such as cancer and other genetic disorder. Many stories have emerged from clinical trials such as the prevention of vision loss, cancer-fighting immune cells, sickle cell treatment, and neuro degradation treatment.
With emerging precision gene editing technology such as the CRISPR system, gene therapy will become much more effective and safer to develop. That’s one of the reasons why I think gene therapy will eventually be utilized in the treatment of disease. Hopefully, we can see the development of an efficient and safe gene therapy soon enough so we can save more lives.
Source
https://academic.oup.com/synbio/article/7/1/ysac027/6809230?searchresult=1
