Gene therapy

the transplantation of normal genes into cells in place of missing or defective ones in order to correct
genetic disorders.

What is gene therapy?

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this
technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using
drugs or surgery. Researchers are testing several approaches to gene therapy, including:

 Replacing a mutated gene that causes disease with a healthy copy of the gene.

 Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

 Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited
disorders, some types of cancer, and certain viral infections), the technique remains risky and is still
under study to make sure that it will be safe and effective. Gene therapy is currently being tested only for
diseases that have no other cures.

How does gene therapy work?

Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to
make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene
therapy may be able to introduce a normal copy of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is
genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can
deliver the new gene by infecting the cell. The viruses are modified so they can't cause disease when
used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the
new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their
DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where
it is taken up by individual cells. Alternately, a sample of the patient's cells can be removed and exposed
to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the
treatment is successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a practical approach
to treating disease. For example, scientists must find better ways to deliver genes and target them to
particular cells. They must also ensure that new genes are precisely controlled by the body.

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a
human cell. If the treatment is successful, the new gene will make a functional protein.
Is gene therapy safe?

Gene therapy is under study to determine whether it could be used to treat disease. Current research is
evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option.
Several studies have already shown that this approach can have very serious health risks, such as
toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be
unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure
that gene therapy research is as safe as possible.

Comprehensive federal laws, regulations, and guidelines help protect people who participate in research
studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy
products in the United States and oversees research in this area. Researchers who wish to test an
approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject
or suspend clinical trials that are suspected of being unsafe for participants.

The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy
research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to
follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at
institutions receiving NIH funding for this type of research must be registered with the NIH Office of
Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH
Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety
issues that warrant further discussion at one of the RAC's public meetings.

An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each
gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical
advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and
approves an institution's potentially hazardous research studies. Multiple levels of evaluation and
oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy
research.

What are the ethical issues surrounding gene therapy?

Because gene therapy involves making changes to the body’s set of basic instructions, it raises many
unique ethical concerns. The ethical questions surrounding gene therapy include:
  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?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells
such as bone marrow or blood cells. This type of gene therapy cannot be passed to a person’s children.
Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the
inserted gene to be passed to future generations. This approach is known as germline gene therapy.

The idea of germline gene therapy is controversial. While it could spare future generations in a family
from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or
have long-term side effects that are not yet known. Because people who would be affected by germline
gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical
concerns, the U.S. Government does not allow federal funds to be used for research on germline gene
therapy in people.

Ethics of Gene Therapy

The concept of changing a person's DNA, even to cure a fatal genetic disease, differs from more
traditional remedies like surgery, pharmaceuticals, and physical therapy, and it is frightening to some
people. Successful treatment approaches are available for a handful of single-gene disorders, most of
which are enzyme deficiencies, including Gaucher's disease (a lysosomal storage disorder) and
phenylketonuria (phenylalanine hydroxylase deficiency). Other disorders, including Duchenne muscular
dystrophy (DMD), are the result of the complete loss of a functional protein. DMD is an X-linked recessive
disorder that is caused by a mutation in the dystrophin gene. Mutation of this gene results in failure of
muscle regeneration, leading to progressive muscle weakness and eventually causing fibrosis in essential
organs (i.e., the heart and diaphragm). At this time, no medical, surgical, or other option exists to correct
the underlying genetic cause of DMD and preserve muscle function in affected males. For individuals with
DMD, the promise of gene therapy through one of the methods listed above means the possibility of
leading a normal life.
Despite such potential benefits, many people oppose gene therapy on religious grounds, believing that
altering genetic material is against God's will. This argument appears to hold the most sway because it
raises the specter of "playing God". Table 1 lists some other frequently debated topics related to the
inclusion of gene therapy in mainstream medical treatment. Many of these questions can be applied to
any type of human research.
Abstract
To discern the ethical issues involved in current gene therapy research, to explore the problems inherent
in possible future gene therapies, and to encourage debate within the scientific community about ethical
questions relevant to both, we surveyed American Society of Human Genetics scientists who engage in
human genetics research. This study of the opinions of U.S. scientific experts about the ethical issues
discussed in the literature on gene therapy contributes systematic data on the attitudes of those working
in the field as well as elaborative comments. Our survey finds that respondents are highly supportive of
the potential use of somatic cell gene therapy to cure serious diseases in adults and children as well as
prospective offspring. A clear majority, however, believe that using such genetic techniques for
enhancement purposes is unacceptable. Delineating the line between disease/disorder and
improvement/enhancement poses a problem not easily resolved and one conducive to the growth of
slippery-slope apprehensions. The majority of respondents also advocate germ-line therapy, in theory at
least, and under similar restrictions, but they recognize the roadblock that the existence of unanticipated
negative consequences currently presents. Another complex matter involves trying to determine
appropriate reasons for choosing target diseases for research, for which the dichotomy between rare
single-gene and common multifactorial diseases reveals an ongoing dilemma.

In: Facts Targeting Disease

What is gene therapy?
Gene therapy is when DNA is introduced into a patient to treat a genetic disease. The new DNA usually
contains a functioning gene to correct the effects of a disease-causing mutation.
Gene therapy uses sections of DNA? (usually genes?) to treat or prevent disease.
The DNA is carefully selected to correct the effect of a mutated gene that is causing disease.
The technique was first developed in 1972 but has, so far, had limited success in treating human
diseases.
Gene therapy may be a promising treatment option for some genetic diseases?, including muscular
dystrophy? and cystic fibrosis?.
There are two different types of gene therapy depending on which types of cells are treated:
Somatic gene therapy: transfer of a section of DNA to any cell of the body that doesn’t produce sperm
or eggs. Effects of gene therapy will not be passed onto the patient’s children.
Germline gene therapy: transfer of a section of DNA to cells that produce eggs or sperm. Effects of gene
therapy will be passed onto the patient’s children and subsequent generations.
Gene therapy techniques
There are several techniques for carrying out gene therapy. These include:
Gene augmentation therapy
This is used to treat diseases caused by a mutation that stops a gene from producing a functioning
product, such as a protein?.
This therapy adds DNA containing a functional version of the lost gene back into the cell.
The new gene produces a functioning product at sufficient levels to replace the protein that was originally
missing.
This is only successful if the effects of the disease are reversible or have not resulted in lasting damage
to the body.
For example, this can be used to treat loss of function disorders such as cystic fibrosis by introducing a
functional copy of the gene to correct the disease (see illustration below).

Gene inhibition therapy

Suitable for the treatment of infectious diseases, cancer and inherited disease caused by inappropriate
gene activity.
The aim is to introduce a gene whose product either:
inhibits the expression of another gene
interferes with the activity of the product of another gene.
The basis of this therapy is to eliminate the activity of a gene that encourages the growth of disease-
related cells.
For example, cancer is sometimes the result of the over-activation of an oncogene? (gene which
stimulates cell growth). So, by eliminating the activity of that oncogene through gene inhibition therapy, it
is possible to prevent further cell growth and stop the cancer in its tracks.

Killing of specific cells

Suitable for diseases such as cancer that can be treated by destroying certain groups of cells.
The aim is to insert DNA into a diseased cell that causes that cell to die.
This can be achieved in one of two ways:
the inserted DNA contains a “suicide” gene that produces a highly toxic product which kills the diseased
cell
the inserted DNA causes expression of a protein that marks the cells so that the diseased cells are
attacked by the body’s natural immune system.
It is essential with this method that the inserted DNA is targeted appropriately to avoid the death of cells
that are functioning normally.

How is DNA transfer done?

A section of DNA/gene containing instructions for making a useful protein is packaged within a vector,
usually a virus?, bacterium? or plasmid?.
The vector acts as a vehicle to carry the new DNA into the cells of a patient with a genetic disease.
Once inside the cells of the patient, the DNA/gene is expressed by the cell’s normal machinery leading to
production of the therapeutic protein and treatment of the patient’s disease.

An illustration to show the transfer of a new gene into the nucleus of a cell via a viral vector. Image credit:
Genome Research Limited
Challenges of gene therapy
Delivering the gene to the right place and switching it on:
it is crucial that the new gene reaches the right cell
delivering a gene into the wrong cell would be inefficient and could also cause health problems for the
patient
even once the right cell has been targeted the gene has to be turned on
cells sometimes obstruct this process by shutting down genes that are showing unusual activity.
Avoiding the immune response:
The role of the immune system is to fight off intruders.
Sometimes new genes introduced by gene therapy are considered potentially-harmful intruders.
This can spark an immune response in the patient, that could be harmful to them.
Scientists therefore have the challenge of finding a way to deliver genes without the immune system
‘noticing’.
This is usually by using vectors that are less likely to trigger an immune response.
Making sure the new gene doesn’t disrupt the function of other genes:
Ideally, a new gene introduced by gene therapy will integrate itself into the genome of the patient and
continue working for the rest of their lives.
There is a risk that the new gene will insert itself into the path of another gene, disrupting its activity.
This could have damaging effects, for example, if it interferes with an important gene involved in
regulating cell division, it could result in cancer.
The cost of gene therapy:
Many genetic disorders that can be targeted with gene therapy are extremely rare.
Gene therapy therefore often requires an individual, case-by-case approach. This may be effective,
but may also be very expensive.
Types of Gene Therapy
Virtually all cells in the human body contain genes, making them potential targets for gene therapy.
However, these cells can be divided into two major categories: somatic cells (most cells of the body) or
cells of the germline (eggs or sperm). In theory it is possible to transform either somatic cells or germ cells.
Gene therapy using germ line cells results in permanent changes that are passed down to subsequent
generations. If done early in embryologic development, such as during preimplantation diagnosis and in
vitro fertilization, the gene transfer could also occur in all cells of the developing embryo. The appeal of
germ line gene therapy is its potential for offering a permanent therapeutic effect for all who inherit the
target gene. Successful germ line therapies introduce the possibility of eliminating some diseases from a
particular family, and ultimately from the population, forever. However, this also raises controversy. Some
people view this type of therapy as unnatural, and liken it to "playing God." Others have concerns about the
technical aspects. They worry that the genetic change propagated by germ line gene therapy may actually
be deleterious and harmful, with the potential for unforeseen negative effects on future generations.
Somatic cells are nonreproductive. Somatic cell therapy is viewed as a more conservative, safer approach
because it affects only the targeted cells in the patient, and is not passed on to future generations. In other
words, the therapeutic effect ends with the individual who receives the therapy. However, this type of
therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived.
Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over
the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene
to the target cells or tissue is also problematic. Regardless of these difficulties, however, somatic cell gene
therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy,
cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially
correcting or treating a life-threatening disorder that may significantly impair a baby's health or development
if not treated before birth.
In summary, the distinction is that the results of any somatic gene therapy are restricted to the actual patient
and are not passed on to his or her children. All gene therapy to date on humans has been directed at
somatic cells, whereas germline engineering in humans remains controversial and prohibited in for instance
the European Union.
Somatic gene therapy can be broadly split into two categories:
ex vivo, which means exterior (where cells are modified outside the body and then transplanted back
in again). In some gene therapy clinical trials, cells from the patient’s blood or bone marrow are
removed and grown in the laboratory. The cells are exposed to the virus that is carrying the desired
gene. The virus enters the cells and inserts the desired gene into the cells’ DNA. The cells grow in
the laboratory and are then returned to the patient by injection into a vein. This type of gene therapy
is called ex vivo because the cells are treated outside the body.
in vivo, which means interior (where genes are changed in cells still in the body). This form of gene
therapy is called in vivo, because the gene is transferred to cells inside the patient’s body.

FIRST GENE THERAPY SUCCESSFUL AGAINST AGING-ASSOCIATED DECLINE: MOUSE

LIFESPAN EXTENDED UP TO 24% WITH A SINGLE TREATMENT

A new study consisting of inducing cells to express telomerase, the enzyme which -- metaphorically --
slows down the biological clock -- was successful. The research provides a "proof-of-principle" that this
"feasible and safe" approach can effectively "improve health span."
A number of studies have shown that it is possible to lengthen the average life of individuals of many
species, including mammals, by acting on specific genes. To date, however, this has meant altering the
animals' genes permanently from the embryonic stage -- an approach impracticable in humans.
Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director Maria ́ Blasco,
have demonstrated that the mouse lifespan can be extended by the application in adult life of a single
treatment acting directly on the animal's genes. And they have done so using gene therapy, a strategy
never before employed to combat aging. The therapy has been found to be safe and effective in mice.
The results were recently published in the journal EMBO Molecular Medicine. The CNIO team, in
collaboration with Eduard Ayuso and Fátima Bosch of the Centre of Animal Biotechnology and Gene
Therapy at the Universitat Autònoma de Barcelona (UAB), treated adult (one-‐year-‐old) and aged (two-‐
year-‐old) mice, with the gene therapy delivering a "rejuvenating" effect in both cases, according to the
authors.
Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by
13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying
the onset of age-‐related diseases -- like osteoporosis and insulin resistance -- and achieving improved
readings on aging indicators like neuromuscular coordination.
The gene therapy consisted of treating the animals with a DNA-modified virus, the viral genes having
been replaced by those of the telomerase enzyme, with a key role in aging. Telomerase repairs the
extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cell's and therefore
the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the
telomerase gene in the cells.
This study "shows that it is possible to develop a telomerase-based anti-aging gene therapy without
increasing the incidence of cancer," the authors affirm. "Aged organisms accumulate damage in their
DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production
can repair or delay this kind of damage," they add.
'Resetting' the biological clock
Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each
time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The
cell, as a result, stops dividing and ages or dies. Telomerase gets around this by preventing telomeres
from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell's biological
clock.
But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few
exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which
divide limitlessly and are therefore immortal -- in fact several studies have shown that telomerase
expression is the key to the immortality of tumour cells.
It is precisely this risk of promoting tumour development that has set back the investigation of
telomerase-‐based anti-‐aging therapies.
In 2007, Blasco's group demonstrated that it was feasible to prolong the lives of transgenic mice, whose
genome had been permanently altered at the embryonic stage, by causing their cells to express
telomerase and, also, extra copies of cancer-‐resistant genes. These animals live 40% longer than is
normal and do not develop cancer.
The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe
this is because the therapy begins when the animals are adult so do not have time to accumulate
sufficient number of aberrant divisions for tumours to appear.
Also important is the kind of virus employed to carry the telomerase gene to the cells. The authors
selected demonstrably safe viruses that have been successfully used in gene therapy treatment of
hemophilia and eye disease. Specifically, they are non-‐replicating viruses derived from others that are
non-‐pathogenic in humans.
This study is viewed primarily as "a proof-‐of-‐principle that telomerase gene therapy is a feasible and
generally safe approach to improve healthspan and treat disorders associated with short telomeres," state
Virginia Boccardi (Second University of Naples) and Utz Herbig (New Jersey Medical School-‐University
Hospital Cancer Centre) in a commentary published in the same journal.
Although this therapy may not find application as an anti-‐aging treatment in humans, in the short term at
least, it could open up a new treatment option for ailments linked with the presence in tissue of
abnormally short telomeres, as in some cases of human pulmonary fibrosis.
More healthy years
As Blasco says, "aging is not currently regarded as a disease, but researchers tend increasingly to view it
as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence
rises with age. In treating cell aging, we could prevent these diseases."
With regard to the therapy under testing, Bosch explains: "Because the vector we use expresses the
target gene (telomerase) over a long period, we were able to apply a single treatment. This might be the
only practical solution for an anti-‐aging therapy, since other strategies would require the drug to be
administered over the patient's lifetime, multiplying the risk of adverse effects."

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In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of
nucleic acid into a patient's cells as a drug to treat disease.[1][2] The first attempt at modifying human
DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in
humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first
therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear
genome was performed by French Anderson in a trial starting in September 1990.

How does gene therapy deliver “good” genes into cells?

A gene cannot be inserted directly into a cell. Instead, a carrier called a vector is genetically engineered to
deliver the gene. Viruses are usually used as the vectors because they are very good at “infecting” cells and
inserting the gene(s) into the cells’ DNA. Types of viral vectors are retrovirus, adenovirus, adeno-associated
virus and herpes simplex virus.

What is the goal of gene therapy?

The goal is to cure a disease or make changes so the body can better fight off disease. It does not correct
100% of your child’s cells. Instead, every time a cell with the “good” gene reproduces, it carries a copy of the
new healthy gene.
 What are the types of gene therapy? APPROACH

The vector can be injected or given by IV directly into a specific tissue. Or a sample of cells can be removed
and exposed to the vector in a laboratory. The cells with the vector are then returned to the patient.

 In vivo gene therapy – the gene is transferred to a patient’s cells while still in the patient.
 Ex vivo gene therapy – the gene is transferred into the cells in a lab and then injected back into the patient.

How does ex vivo gene therapy work?

1) Stem cells are collected in one of two ways: by bone marrow aspiration, or by purifying blood drawn
through a central line in a process called apheresis.

2) Before the infusion, most children have chemotherapy. This makes room for the new cells by getting rid of
the existing cells in the bone marrow.

3) In the laboratory, the stem cells from the blood or bone marrow are exposed to a virus or other type of
vector containing the desired genes.
4) Once the stem cells take up the vector and merge the genes into cells’ DNA, the cells are given back to the
patient in an IV infusion.