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The Future of Gene Therapy Used for Complex Diseases


As early as in 1972, the famous American biologists Friedmann and Roblin has put forward the concept of gene therapy in Science magazine.

Gene therapy in a broad sense refers to the use of molecular biology methods to introduce target genes into patients, to express them, correct or compensate for diseases caused by genetic defects and abnormalities. Or increase the expression of the target gene (gene activation) to achieve the purpose of treating disease.

Since the first gene therapy clinical trial in the 1990s, this technology has made a lot of progress. However, the impact of gene therapy has always been limited, which is a practical problem that has to be faced.

Technical limitations mean that gene therapy is limited to rare diseases caused by mutations in a single gene, and also limited to certain parts of the body, such as the eyes and liver.

The delivery system of gene therapy

Gene therapy vectors are divided into two categories: viral vectors (mainly including lentivirusadenovirus, retrovirus, adeno-associated virus, etc.), non-viral vectors (mainly including naked DNA, liposomes, nanocarriers, etc.)

The Next-generation of gene therapy

According to Kuzmin, so far there have been three generations of gene therapy technology. The first generation is a typical single gene replacement, such as Luxturna, which sends DNA fragments with normal functions into the cell, replacing and covering disease-causing mutant genes to repair specific gene mutations that cause blindness.

The second generation includes the use of gene therapy to introduce new functions. For example, Kymriah, an autologous T cell immunotherapy based on genetic modification. In 2017, the FDA approved its use for the treatment of acute lymphoblastic leukemia in some children and youth. After extracting the patient’s T cells, the therapy uses genetic modification to load a specific protein, the chimeric antigen receptor (CAR), into the T cells to help them hunt down cancer cells.

The third generation may be the key to unlocking the full potential of gene therapy. It incorporates some other technologies that can introduce a new drug target into the patient’s body, making it possible to open, close, and adjust the intensity of treatment.

For brain disease

For a long time, the treatment of brain diseases has been a huge medical challenge, such as epilepsy.

“Epilepsy affects 1% of the entire population, and about 30% of epilepsy patients continue to have seizures despite receiving medical treatment,” said Professor Dimitry Kullmann of UCL. “This is a paradox. Our understanding of the mechanism behind epilepsy is good, but in a considerable part of epilepsy patients, we cannot suppress the onset of the disease. The reason is that the existing drugs are not targeted to the epilepsy area of ​​the brain, but “bath” the entire body. These drugs cannot be distinguished neurons and synapses that cause seizures, and parts of the brain responsible for memory, sensory function, motor function, and balance. ”

Gene therapy can solve this problem; it can be injected directly into the brain area that causes seizures. In addition, using DNA sequences called promoters, it is possible to limit the effects of gene therapy to specific neurons in this region. It is known that excessive activity of excitatory neurons can cause seizures, and gene therapy can reduce the activity of excitatory neurons in the onset.

Another method research team is testing is chemical genetics. Kullmann said: “Our idea is to use gene therapy to implant a special receptor into neurons. This receptor is designed to respond to a drug. Treating patients with this drug can reduce neuronal activity and thus Suppress seizures. ”

“The advantage of this method is that you can start or end the treatment only with or without medication as needed. It can be adjusted according to the specific conditions of each patient, so it can make gene therapy more accurate. In addition, it also reduces the huge challenge of ensuring that the correct dose is obtained in a one-time treatment. “Kullmann explained.

Ultimately, this technology allows scientists to target various diseases under the “shield” of epilepsy, not just a special form of disease caused by gene mutations. It can be promoted for other diseases involving the brain, such as Parkinson’s disease, amyotrophic lateral sclerosis, and pain. However, this research is still in its infancy, and it will take some time to prove its potential in humans.

For eye disease

Blindness has always been the main goal of gene therapy because the eye is the ideal target for this technology. The activity of the immune system is suppressed in the eye, thereby minimizing the chance of treatment rejection. In addition, unlike other cells in the body, those cells involved in vision are not updated over time, so that the injected DNA can be retained for several years.

However, hundreds of mutations that can cause blindness. If classic gene therapy is used, then for each mutation, a different treatment must be developed from scratch. Some companies only do this for the most common mutant genes that cause blindness, and many other less common mutations are ignored. Other companies are turning to a new generation of gene therapy technology.

Bernard Gilly, CEO of GenSight, a biotechnology company in Paris, France, said: “We found it very difficult to use classic gene therapy methods in each individual mutation. GenSight is developing new gene therapies to treat blindness.”

Specifically, GenSight is using optogenetics (following principles similar to gene therapy. Optogenetics technology includes introducing light-responsive proteins into cells) to develop a monotherapy for the treatment of retinitis pigmentosa. This genetic disease may be caused by mutations in any of more than 200 genes, and due to the degradation of photoreceptor cells that sense light and send signals to the brain, patients will experience progressive vision loss.

With optogenetics, it is possible to transfer the lost photoreceptor function to the cells in the retina responsible for transmitting visual information to the brain. The company is currently testing this method in clinical trials. They combined gene therapy with a specially developed external wearable device (designed as goggles) to amplify the stimulation of light to the transduced nerve cells, thereby helping those who are blind due to retinitis pigmentosa to restore their vision.

Optogenetics does not create miracles, but it may restore people’s ability to navigate autonomously in unknown environments to some extent. According to Gilly, identifying faces will be a more challenging goal in the future.

Nonetheless, the potential of optogenetics to solve multiple genetic mutation problems with a single treatment may be revolutionary. As long as the neurons responsible for sending light signals to the brain are intact, this method can be generalized to other forms of blindness. In addition, this method can also be used to treat brain diseases such as epilepsy, Parkinson’s disease, or amyotrophic lateral sclerosis through irradiation of target neurons with implants.

However, the method of applying optogenetics to the brain is still under further study. Although this technology has been in existence for more than 20 years, its application in humans is still very limited and is still in the early research stage.


Chemical genetics and optogenetics are just two representatives of a wave of new technologies that address the limitations of gene therapy. Other methods are also being developed, such as thermal genetics, whose innovation lies in the use of temperature to control neurons, including the introduction of proteins activated by the heat generated by infrared light.

With more and more tools available, it is easier than ever for scientists to develop new gene therapies to address the specific challenges affecting different diseases in various parts of the body. Traditionally, gene therapy such as heart, lung, or pancreas is particularly difficult to target, but now, this situation may soon end. Gene therapy will benefit patients in larger and broader indications. The expansion of gene therapy into the mainstream disease field will elevate precision medicine to a whole new level.

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