LESSON 4: GENE THERAPY

Site: King's College of the Philippines

Course: SCIENCE TECHNOLOGY and SOCIETY
Book: LESSON 4: GENE THERAPY
Printed by: Jake Cogoy
Date: Sunday, 26 December 2021, 8:50 PM
Description
Gene therapy, also called gene transfer therapy, introduction of a normal gene into an
individual’s genome in order to repair a mutation that causes a genetic disease. When a normal
gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a
chromosomal site different from the defective allele; although that may repair the mutation, a
new mutation may result if the normal gene integrates into another functional gene. If the normal
gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and
produce enough normal gene product for the entire body to be restored to the undiseased
phenotype (Rogers, 2021).

ADDITIONAL SOURCE:
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Table of contents
1. LESSON 4: Gene Therapy
1. LESSON 4: Gene Therapy
LESSON 4. GENE THERAPY

Gene therapy, also called gene transfer therapy, introduction of a normal gene into an
individual’s genome in order to repair a mutation that causes a genetic disease. When a normal
gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a
chromosomal site different from the defective allele; although that may repair the mutation, a
new mutation may result if the normal gene integrates into another functional gene. If the normal
gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and
produce enough normal gene product for the entire body to be restored to the undiseased
phenotype (Rogers, 2021).

A. Learning Outcomes: At the end of the lesson, you will be able to:

describe gene therapy and its various forms;

discuss the prevalence of gene therapy in daily life; and
explore the opportunities that may be opened by gene therapy in the future.
B. Key Concepts

1. INTRODUCTION TO GENE THERAPY

When identifying the contribution of technology to biology, the first place to look would be the
field of human health. The whole vast concerns of human health including aging, disease
treatment and prevention, diet and general lifestyle have greatly benefited from technology.

Human gene therapy was first realized in 1971 when the first recombinant DNA experiments
were planned. In 2015, a team of researchers at the Harvard Medical School and the Boston
Children`s Hospital stated that they were able to restore basic hearing in genetically deaf mice
using gene therapy. The Boston Children`s Hospital research team also reported that they have
restored a higher level of hearing-down to 25 decibels.

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic
fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe
combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may
reverse the symptoms of disease in the treated individual, but the modification is not passed on
to the next generation. Germline gene therapy aims to place corrected cells inside the germ line
(e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and
provide a normal gametic contribution to the next generation. Germline gene therapy has been
achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy.
In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1
antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver
disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and
then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected
cells functioned normally (Griffiths, 2021).

a. Prerequisites for Gene Therapy

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically
referred to as a viral vector) for the gene, demonstrating that the transferred gene can express
itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene
therapy in humans have satisfied all those conditions, often because the delivery system fails to
reach cells or the genes are not expressed by cells. Improved gene therapy systems are being
developed by using nanotechnology. A promising application of that research involves
packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells
specifically and leaving healthy cells unharmed (Encyclopedia Britannica, 2021).

b. Ethical and Safety Concerns

Some aspects of gene therapy, including genetic manipulation and selection, research on
embryonic tissue, and experimentation on human subjects, have aroused ethical controversy
and safety concerns. Some objections to gene therapy are based on the view that humans
should not “play God” and interfere in the natural order. On the other hand, others have argued
that genetic engineering may be justified where it is consistent with the purposes of God as
creator. Some critics are particularly concerned about the safety of germline gene therapy,
because any harm caused by such treatment could be passed to successive generations.
Benefits, however, would also be passed on indefinitely. There also has been concern that the
use of somatic gene therapy may affect germ cells (Harris, 2021).

2. GENE THERAPY AND ITS PROCESS

a. Gene therapy is used to correct defective genes in order to cure a disease or help your body
better fight disease.

Researchers are investigating several ways to do this, including:

Replacing mutated genes. Some cells become diseased because certain genes work incorrectly
or no longer work at all. Replacing the defective genes may help treat certain diseases. For
instance, a gene called p53 normally prevents tumor growth. Several types of cancer have been
linked to problems with the p53 gene. If doctors could replace the defective p53 gene, that might
trigger the cancer cells to die.
Fixing mutated genes. Mutated genes that cause disease could be turned off so that they no
longer promote disease, or healthy genes that help prevent disease could be turned on so that
they could inhibit the disease.
Making diseased cells more evident to the immune system. In some cases, your immune
system doesn't attack diseased cells because it doesn't recognize them as intruders. Doctors
could use gene therapy to train your immune system to recognize the cells that are a threat
(Mayo Clinic, 2021).
b. Process

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical
trials are research studies that help doctors determine whether a gene therapy approach is safe
for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy
being used.

For example, in one type of gene therapy:

You may have blood drawn or you may need bone marrow removed from your hipbone with a
large needle.
Then, in a lab, cells from the blood or bone marrow are exposed to a virus or another type of
vector that contains the desired genetic material.
Once the vector has entered the cells in the lab, those cells are injected back into your body into
a vein or into tissue, where your cells take up the vector along with the altered genes.
c. Risks
Gene therapy has some potential risks. A gene can't easily be inserted directly into your cells.
Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells
and carry genetic material into the cells' genes. Researchers remove the original disease-
causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

Unwanted immune system reaction. Your body's immune system may see the newly introduced
viruses as intruders and attack them. This may cause inflammation and, in severe cases, organ
failure.
Targeting the wrong cells. Because viruses can affect more than one type of cells, it's possible
that the altered viruses may infect additional cells — not just the targeted cells containing
mutated genes. If this happens, healthy cells may be damaged, causing other illness or
diseases, such as cancer.
Infection caused by the virus. It's possible that once introduced into the body, the viruses may
recover their original ability to cause disease.
Possibility of causing a tumor. If the new genes get inserted in the wrong spot in your DNA,
there is a chance that the insertion might lead to tumor formation.
Viruses aren't the only vectors that can be used to carry altered genes into your body's cells.
Other vectors being studied in clinical trials include:
Stem cells. Stem cells are the cells from which all other cells in your body are created. For gene
therapy, stem cells can be trained in a lab to become cells that can help fight disease.
Liposomes. These fatty particles have the ability to carry the new, therapeutic genes to the
target cells and pass the genes into your cells' DNA (Mayo Clinic, 2021).
d. Gene therapy can be simply viewed as the insertion of foreign DNA into a patient`s tissue that
hope to successfully eradicate the targeted disease.

There are several processes of gene therapy. These are the following:

Replacement of mutated gene that causes disease with a healthy copy of the gene.
Inactivation of a mutated gene that is functioning improperly.
Introducing a new gene into the body to help fight a disease.
A gene cannot be directly inserted into the human body it is with the use of a carrier or vector.
The vector which is normally used are viruses that have been genetically changed to carry
normal DNA.
3. APPLICATION OF GENE THERAPY

It is used in the replacement of genes that cause medical ill-health

The method generally destroys the problem causing genes
It helps the body to fight against diseases by adding genes to the human body
This method is employed to treat diseases such as cancer, ADA deficiency, cystic fibrosis, etc.
4. TYPES OF GENE THERAPY
SOMATIC GENE THERAPY involves the manipulation of the genes in cells that will be helpful
to the patient but not inherited to the next generation.
GERM-LINE GENE THERAPY involves the genetic modification of germ cells or the origin cells
that will pass the change on to the next generation.
STEM CELL GENE THERAPY are mother cells that have the potential to become any type of
cell in the body. The characteristic of stem cells is its ability to self-renew or multiply while
maintaining the potential to develop into other types of cells.
5. SOURCES OF STEM CELLS

EMBRYONIC STEM CELL- derived from a four or five-day old human embryo.
SOMATIC STEM CELL- these are cells that exist throughout the body after embryonic
development and are found inside of different types of tissue.
6. THE BIOETHICS OF GENE THERAPY

There are ethical issues involved in gene therapy. Some of the inquires cited are (Genetic
Home Reference, 2017):

How can ―good and ―bad uses of gene therapy be distinguished?

Who decides which traits are normal and which constitute a disability or disorder?
Will the high costs of gene therapy make it available only to the wealthy?
Could the widespread use of gene therapy make society less accepting of people who are
different?
Should people be allowed to use gene therapy to enhance basic human traits such as height,
intelligence, or athletic ability?
7. ADVERSE EFFECTS, CONTRAINDICATIONS AND HURDLES FOR USE

Some of the unsolved problems include:

Short-lived nature – Before gene therapy can become a permanent cure for a condition, the
therapeutic DNA introduced into target cells must remain functional and the cells containing the
therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the genome
and the rapidly dividing nature of many cells prevent it from achieving long-term benefits.
Patients require multiple treatments.
Immune response – Any time a foreign object is introduced into human tissues, the immune
system is stimulated to attack the invader. Stimulating the immune system in a way that reduces
gene therapy effectiveness is possible. The immune system's enhanced response to viruses
that it has seen before reduces the effectiveness to repeated treatments.
Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses,
and gene control and targeting issues.
Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood
pressure, Alzheimer's disease, arthritis, and diabetes, are affected by variations in multiple
genes, which complicate gene therapy.
Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the
testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the
latter practice.
Insertional mutagenesis – If the DNA is integrated in a sensitive spot in the genome, for
example in a tumor suppressor gene, the therapy could induce a tumor. This has occurred in
clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which
hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and
this led to the development of T cell leukemia in 3 of 20 patients. One possible solution is to add
a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since
the longer the DNA is, the harder it is to integrate into cell genomes. CRISPR technology allows
researchers to make much more precise genome changes at exact locations.
Cost – Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient, was
reported in 2013 to be the world's most expensive drug.
Deaths
Three patients' deaths have been reported in gene therapy trials, putting the field under close
scrutiny. The first was that of Jesse Gelsinger, who died in 1999 because of immune rejection
response. One X-SCID patient died of leukemia in 2003. In 2007, a rheumatoid arthritis patient
died from an infection; the subsequent investigation concluded that the death was not related to
gene therapy (Hogarth, & Miller, et al. 2009).

8. REGULATIONS

Regulations covering genetic modification are part of general guidelines about human-involved
biomedical research. There are no international treaties which are legally binding in this area,
but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects)
was amended by the World Medical Association's General Assembly in 2008. This document
provides principles physicians and researchers must consider when involving humans as
research subjects. The Statement on Gene Therapy Research initiated by the Human Genome
Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGO's document
emphasizes human freedom and adherence to human rights, and offers recommendations for
somatic gene therapy, including the importance of recognizing public concerns about such
research (HUGO Ethics Committee, 2001).