GENE THERAPY

MODULE 11
What is Gene Therapy?

A wide range of diseases such as cystic fibrosis, cancer, diabetes,

heart disease, AIDS, andhemophilia are caused by genetic
irregularities or deformities (Yazdani et al., 2018). Gene therapy is
anexperimental technique developed in order to treat these diseases.
Gene therapy is the introduction,removal, or alteration of genetic
material in order to prevent or treat a disease
How Does Gene Therapy Work?

Ideally, gene therapy may someday allow doctors to treat disorders by inserting or
replacing genes into a patient’s cells instead of through surgery or drugs (U.S. National
Library of Medicine, 2020). There are various approaches in performing gene therapy,
including:

a. Replacing a disease-causing mutated gene with a healthy copy of the gene

b. Inactivating or “silencing” a mutated gene or a gene that is not functioning properly

c. Introducing a new gene into the body to help counteract or fight the disease

d. Correcting the sequence of a mutated gene

Replacing A Mutated Gene (GENE REPLACEMENT)In order to replace a problematic
or mutated gene:

• A functional and healthy gene will be inserted to a viral vector

• The viral vector will carry and place the healthy gene on the site of mutation

• The mutated non-functional gene will be “spliced” or cut and removed

• The healthy gene will be attached and becomes a part of the final DNA strand
Gene silencing or gene knockdown

This method aims to repress or turn off the function of a mutated

gene which prevents thecells from producing disease-causing
proteins. Gene silencing reduces the expression of a diseasecausing
gene (Hood, 2004; Mocellin & Provenzano, 2004). It can be done by:

a. inserting a repressor a.k.a silencer gene that reduces or prevents

the expression of themutated gene

b. b. editing the gene to make it impossible for it to produce the

protein it codes for

This method aims to repress or turn off the function of a mutated

gene which prevents thecells from producing disease-causing
proteins. Gene silencing reduces the expression of a diseasecausing
gene (Hood, 2004; Mocellin & Provenzano, 2004). It can be done
by:a. inserting a repressor a.k.a silencer gene that reduces or
prevents the expression of themutated geneb. editing the gene to
make it impossible for it to produce the protein it codes for
Introducing a New Gene (GENE ADDITION)

In gene addition, new and functional genes are introduced or added into the
genome to help
fight or prevent a disease (Pharmaphorum, 2019).

The introduction of a new gene can also be used to kill specific

diseased cells. This is useful for diseases like cancer.

There are two ways to do this:

1. by inserting a gene called the suicide gene into the diseased

cells that will cause the cells
to die

2. by inserting a gene that will cause the cells to produce a

protein that will mark them as a
target for the body’s natural immune system response.
Correcting the sequence of a mutated gene (GENE EDITING)

In gene editing, instead of replacing the whole gene, the specific error is
located and edited.
Two types of Gene Therapy

There are two distinct types of gene therapy, depending on the nature of the target
cells:

Somatic and Germline Gene Therapy. If the target cells are anybody cells except the
sperm and egg cell and the cell that produce them, this is Somatic Gene Therapy. When
the cells targeted are either sperm or egg cells, this
is Germline Gene Therapy (Chatterjee, Singh, & Saluja, 2013).
Somatic Gene Therapy

This type of gene therapy is effective in treating diseases like muscular dystrophy,
cystic fibrosis, cancer, and some infectious diseases. The effects of this method are
short-lived and will not be passed on to the next generation. So, the children of a
patient treated using somatic gene therapy are still at risk of contracting the diseases.
Somatic Gene Therapy can be done ex vivo (outside the body) or in vivo (inside the body)
Germline Gene Therapy

In Germline Gene Therapy, on the other hand, the cells that produce the
reproductive cells or sex cells (the egg or sperm) are modified, and all the cells
of the resulting embryo will possess the edited gene. The effect of removing or
correcting the disease will be passed on to the patient’s children as well as the
generations after them. Therefore, there is a possibility of permanently
removing an inherited disorder or disease from a family line. As of 2014, about
40 countries have discouraged or banned research on Germline Gene Therapy
(Araki & Ishii, 2014). It is currently not allowed to be done on humans because
of ethical and safety concerns and issues regarding possible permanent changes
in human genes.
Challenges Associated with Gene Therapy
While Gene Therapy is no doubt a
breakthrough in science and medicine, there
are several challenges to its success and
problems that can be associated with it.
A. Gene Delivery and Activation

In most cases, a therapeutic gene needs to be delivered not just to a single cell but to
groups of cells or tissues. This requires an accurate and specific gene delivery.
Otherwise, gene therapy may be useless. After arriving at the correct target cells, the
genes must also be “turned on” and have to remain “on”. However, cells can have the
tendency to “turn off” certain genes when there are already too many active genes.

In some cases, delivered genes may also be overactivated, causing their overexpression.
The overproduction of enzymes or proteins due to this overactivation may lead to other
health issues and problems.
B. The Body’s Immune Response

Our immune system is naturally inclined to attack any foreign intruders like viruses and
bacteria. Because gene therapy uses viral vectors to transport genes, they need to be
able to avoid the body’s immune system to prevent it from attacking them. This is often
challenging to do.

Additionally, the treatment effects are often short-lived, so patients will need to undergo
multiple rounds of gene therapy. However, if the patient’s immunity is low due to gene
therapy, there is a risk for the disease to progress or get worse. This makes it even more
difficult to repeat gene therapy
C. Impact to Non-Target Genes and Cells

While very small, there is also a risk of attaching or inserting

modified genes into the wrong part of the genome or the wrong cell,
which can lead to a series of reactions that can cause cell death.
This may also negatively affect the function of surrounding healthy
cells.

Viral vectors also tend to disrupt vital genes, possibly leading to

another disease or predisposition to other diseases like cancer.
This can also trigger inflammatory, toxicity, or immune responses.
Other cells may also be targeted aside from the target cells
D. Limited Access and Commercial Availability

Many genetic diseases are not common. For rare diseases, gene therapy
should be individualized and customized to every patient to ensure
effectiveness. This makes developing and administering gene therapy very
expensive

Even for more common genetic disorders and related diseases like cancer,
gene therapy is still more costly than other treatment options. Because of
this, many people cannot afford and do not have access to gene therapy.
E. Multi-gene Disorders

Multiple genes with different functions control genetic disorders

like high blood pressure,heart disease, arthritis, diabetes, and
Alzheimer’s disease. So, to treat these diseases, many genes
may have to be corrected, deleted, or replaced. Doing so may
lead to complicated reactions in the body or possibly even more
dangerous diseases
Thank you!!!