the future of gene therapy used for complex diseases

1. The Future of Gene Therapy Used for Complex
Diseases
Introduction
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 lentivirus, adenovirus, retrovirus, adeno-associated virus, etc.), non-
viral vectors (mainly including naked DNA, liposomes, nanocarriers, etc.)

2. 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

3. 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 diseasesunder 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

4. 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.
Summary
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.