Gene Therapy

Gene therapy is a rapidly growing field of medicine in which genes

are introduced into the body to treat diseases. Genes control
heredity and provide the basic biological code for determining a
cell's specific functions. Gene therapy seeks to provide genes that
correct or supplant the disease-controlling functions of cells that are
not, in essence, doing their job. Somatic gene therapy introduces
therapeutic genes at the tissue or cellular level to treat a specific
individual. Germ-line gene therapy inserts genes into reproductive
cells or possibly into embryos to correct genetic defects that could
be passed on to future generations. Initially conceived as an
approach for treating inherited diseases, like cystic fibrosisand
Huntington's disease, the scope of potential gene therapies has
grown to include treatments for cancers, arthritis, and infectious
diseases. Although gene therapy testing in humans has advanced
rapidly, many questions surround its use. For example, some
scientists are concerned that the therapeutic genes themselves may
cause disease. Others fear that germ-line gene therapy may be
used to control human development in ways not connected with
disease, like intelligence or appearance.

The biological basis of gene therapy

Gene therapy has grown out of the science of genetics or how
heredity works. Scientists know that life begins in a cell, the basic
building block of all multicellular organisms. Humans, for instance,
are made up of trillions of cells, each performing a specific function.
Within the cell's nucleus (the center part of a cell that regulates its
chemical functions) are pairs of chromosomes. These threadlike
structures are made up of a single molecule of DNA
(deoxyribonucleic acid), which carries the blueprint of life in the form
of codes, or genes, that determine inherited characteristics.

A DNA molecule looks like two ladders with one of the sides taken
off both and then twisted around each other. The rungs of these
ladders meet (resulting in a spiral staircase-like structure) and are
called base pairs. Base pairs are made up of nitrogen molecules
and arranged in specific sequences. Millions of these base pairs, or
sequences, can make up a single gene, specifically defined as a
segment of the chromosome and DNA that contains certain
hereditary information. The gene, or combination of genes formed
by these base pairs ultimately direct an organism's growth and
characteristics through the production of certain chemicals, primarily
proteins, which carry out most of the body's chemical functions and
biological reactions.

Scientists have long known that alterations in genes present within

cells can cause inherited diseases like cystic fibrosis, sickle-cell
anemia, and hemophilia. Similarly, errors in the total number of
chromosomes can cause conditions such as Down syndrome or
Turner's syndrome. As the study of genetics advanced, however,
scientists learned that an altered genetic sequence also can make
people more susceptible to diseases, like atherosclerosis,
cancer, and even schizophrenia. These diseases have a genetic
component, but also are influenced by environmental factors (like
diet and lifestyle). The objective of gene therapy is to treat diseases
by introducing functional genes into the body to alter the cells
involved in the disease process by either replacing missing genes or
providing copies of functioning genes to replace nonfunctioning
ones. The inserted genes can be naturally-occurring genes that
produce the desired effect or may be genetically engineered (or
altered) genes.

Scientists have known how to manipulate a gene's structure in the

laboratory since the early 1970s through a process called gene
splicing. The process involves removing a fragment of DNA
containing the specific genetic sequence desired, then inserting it
into the DNA of another gene. The resultant product is called
recombinant DNA and the process is genetic engineering.

There are basically two types of gene therapy. Germ-line gene

therapy introduces genes into reproductive cells (sperm and eggs)
or someday possibly into embryos in hopes of correcting genetic
abnormalities that could be passed on to future generations. Most of
the current work in applying gene therapy, however, has been in the
realm of somatic gene therapy. In this type of gene therapy,
therapeutic genes are inserted into tissue or cells to produce a
naturally occurring protein or substance that is lacking or not
functioning correctly in an individual patient.

Viral vectors
In both types of therapy, scientists need something to transport
either the entire gene or a recombinant DNA to the cell's nucleus,
where the chromosomes and DNA reside. In essence, vectors are
molecular delivery trucks. One of the first and most popular vectors
developed were viruses because they invade cells as part of the
natural infection process. Viruses have the potential to be excellent
vectors because they have a specific relationship with the host in
that they colonize certain cell types and tissues in specific organs.
As a result, vectors are chosen according to their attraction to
certain cells and areas of the body.
One of the first vectors used was retroviruses. Because these
viruses are easily cloned (artificially reproduced) in the laboratory,
scientists have studied them extensively and learned a great deal
about their biological action. They also have learned how to remove
the genetic information that governs viral replication, thus reducing
the chances of infection.

Retroviruses work best in actively dividing cells, but cells in the body
are relatively stable and do not divide often. As a result, these cells
are used primarily for ex vivo (outside the body) manipulation. First,
the cells are removed from the patient's body, and the virus, or
vector, carrying the gene is inserted into them. Next, the cells are
placed into a nutrient culture where they grow and replicate. Once
enough cells are gathered, they are returned to the body, usually by
injection into the blood stream. Theoretically, as long as these cells
survive, they will provide the desired therapy.

Another class of viruses, called the adenoviruses, also may prove to

be good gene vectors. These viruses can effectively infect
nondividing cells in the body, where the desired gene product then
is expressed naturally. In addition to being a more efficient
approach to gene transportation, these viruses, which cause
respiratory infections, are more easily purified and made stable than
retroviruses, resulting in less chance of an unwanted viral infection.
However, these viruses live for several days in the body, and some
concern surrounds the possibility of infecting others with the viruses
through sneezing or coughing. Other viral vectors
include influenza viruses, Sindbis virus, and a herpes virus that
infects nerve cells.

Scientists also have delved into nonviral vectors. These vectors rely
on the natural biological process in which cells uptake (or gather)
macromolecules. One approach is to use liposomes, globules of fat
produced by the body and taken up by cells. Scientists also are
investigating the introduction of raw recombinant DNA by injecting it
into the bloodstream or placing it on microscopic beads of gold shot
into the skin with a "gene-gun." Another possible vector under
development is based on dendrimer molecules. A class of polymers
(naturally occurring or artificial substances that have a
high molecular weight and formed by smaller molecules of the same
or similar substances), is "constructed" in the laboratory by
combining these smaller molecules. They have been used in
manufacturing Styrofoam, polyethylene cartons, and Plexiglass. In
the laboratory, dendrimers have shown the ability to transport
genetic material into human cells. They also can be designed to
form an affinity for particular cell membranes by attaching to certain
sugars and protein groups.

The history of gene therapy

In the early 1970s, scientists proposed "gene surgery" for treating
inherited diseases caused by faulty genes. The idea was to take out
the disease-causing gene and surgically implant a gene that
functioned properly. Although sound in theory, scientists, then and
now, lack the biological knowledge or technical expertise needed to
perform such a precise surgery in the human body.

However, in 1983, a group of scientists from Baylor College of

Medicine in Houston, Texas, proposed that gene therapy could one
day be a viable approach for treating Lesch-Nyhan disease, a rare
neurological disorder. The scientists conducted experiments in
which an enzyme-producing gene (a specific type of protein) for
correcting the disease was injected into a group of cells for
replication. The scientists theorized the cells could then be injected
into people with Lesch-Nyhan disease, thus correcting the genetic
defect that caused the disease.
As the science of genetics advanced throughout the 1980s, gene
therapy gained an established foothold in the minds of medical
scientists as a promising approach to treatments for specific
diseases. One of the major reasons for the growth of gene
therapy was scientists' increasing ability to identify the specific
genetic malfunctions that caused inherited diseases. Interest grew
as further studies of DNA and chromosomes (where genes reside)
showed that specific genetic abnormalities in one or more genes
occurred in successive generations of certain family members who
suffered from diseases like intestinal cancer, bipolar disorder,
Alzheimer's disease, heart disease, diabetes, and many more.
Although the genes may not be the only cause of the disease in all
cases, they may make certain individuals more susceptible to
developing the disease because of environmental influences,
like smoking, pollution, and stress. In fact, some scientists theorize
that all diseases may have a genetic component.

On September 14, 1990, a four-year old girl suffering from a genetic

disorder that prevented her body from producing a crucial enzyme
became the first person to undergo gene therapy in the United
States. Because her body could not produce adenosine deaminase
(ADA), she had a weakened immune system, making her extremely
susceptible to severe, life-threatening infections. W. French
Anderson and colleagues at the National Institutes of Health's
Clinical Center in Bethesda, Maryland, took white blood cells (which
are crucial to proper immune system functioning) from the girl,
inserted ADA producing genes into them, and then transfused the
cells back into the patient. Although the young girl continued to
show an increased ability to produce ADA, debate arose as to
whether the improvement resulted from the gene therapy or from an
additional drug treatment she received.
Nevertheless, a new era of gene therapy began as more and more
scientists sought to conduct clinical trial (testing in
humans) research in this area. In that same year, gene therapy was
tested on patients suffering from melanoma (skin cancer). The goal
was to help them produce antibodies (disease fighting substances
in the immune system) to battle the cancer.

These experiments have spawned an ever growing number of

attempts at gene therapies designed to perform a variety of
functions in the body. For example, a gene therapy for cystic fibrosis
aims to supply a gene that alters cells, enabling them to produce a
specific protein to battle the disease. Another approach was used
for brain cancer patients, in which the inserted gene was designed
to make the cancer cells more likely to respond to drug treatment.
Another gene therapy approach for patients suffering from artery
blockage, which can lead to strokes, induces the growth of new
blood vessels near clogged arteries, thus ensuring normal blood
circulation.

Currently, there are a host of new gene therapy agents in clinical

trials. In the United States, both nucleic acid based (in vivo )
treatments and cell-based (ex vivo ) treatments are being
investigated. Nucleic acid based gene therapy uses vectors (like
viruses) to deliver modified genes to target cells. Cell-based gene
therapy techniques remove cells from the patient in order to
genetically alter them then reintroduce them to the patient's body.
Presently, gene therapies for the following diseases are being
developed: cystic fibrosis (using adenoviral vector), HIV infection
(cell-based), malignant melanoma (cell-based),
Duchenne muscular dystrophy (cell-based), hemophilia B (cell-
based), kidney cancer (cell-based), Gaucher's Disease (retroviral
vector), breast cancer (retroviral vector), and lung cancer (retroviral
vector). When a cell or individual is treated using gene therapy and
successful incorporation of engineered genes has occurred, the cell
or individual is said to be transgenic.

The medical establishment's contribution to transgenic research has

been supported by increased government funding. In 1991, the U.S.
government provided $58 million for gene therapy research, with
increases in funding of $15-40 million dollars a year over the
following four years. With fierce competition over the promise of
societal benefit in addition to huge profits, large pharmaceutical
corporations have moved to the forefront of transgenic research. In
an effort to be first in developing new therapies, and armed with
billions of dollars of research funds, such corporations are making
impressive strides toward making gene therapy a viable reality in
the treatment of once elusive diseases.

Diseases targeted for treatment by gene therapy

The potential scope of gene therapy is enormous. More than 4,200
diseases have been identified as resulting directly from abnormal
genes, and countless others that may be partially influenced by a
person's genetic makeup. Initial research has concentrated on
developing gene therapies for diseases whose genetic origins have
been established and for other diseases that can be cured or
improved by substances genes produce.

The following are examples of potential gene therapies. People

suffering from cystic fibrosis lack a gene needed to produce a salt-
regulating protein. This protein regulates the flow of chloride into
epithelial cells, (the cells that line the inner and outer skin layers)
that cover the air passages of the nose and lungs. Without this
regulation, patients with cystic fibrosis build up a thick mucus that
makes them prone to lung infections. A gene therapy technique to
correct this abnormality might employ an adenovirus to transfer a
normal copy of what scientists call the cystic fibrosis
transmembrane conductance regulator, or CTRF, gene. The gene is
introduced into the patient by spraying it into the nose or
lungs. Researchers announced in 2004 that they had, for the first
time, treated a dominant neurogenerative disease called
Spinocerebella ataxia type 1, with gene therapy. This could lead to
treating similar diseases such as Huntingtons disease. They also
announced a single intravenous injection could deliver therapy to all
muscles, perhaps providing hope to people with muscular
dystrophy.

Familial hypercholesterolemia (FH) also is an inherited disease,

resulting in the inability to process cholesterol properly, which leads
to high levels of artery-clogging fat in the blood stream. Patients
with FH often suffer heart attacks and strokes because of blocked
arteries. A gene therapy approach used to battle FH is much more
intricate than most gene therapies because it involves partial
surgical removal of patients' livers (ex vivo transgene therapy).
Corrected copies of a gene that serve to reduce cholesterol build-up
are inserted into the liver sections, which then are transplanted back
into the patients.

Gene therapy also has been tested on patients with AIDS. AIDS is
caused by the human immunodeficiency virus (HIV), which
weakens the body's immune system to the point that sufferers are
unable to fight off diseases like pneumonias and cancer. In one
approach, genes that produce specific HIV proteins have been
altered to stimulate immune system functioning without causing the
negative effects that a complete HIV molecule has on the immune
system. These genes are then injected in the patient's blood
stream. Another approach to treating AIDS is to insert, via white
blood cells, genes that have been genetically engineered to produce
a receptor that would attract HIV and reduce its chances of
replicating. In 2004, researchers reported that had developed a new
vaccine concept for HIV, but the details were still in development.

Several cancers also have the potential to be treated with gene

therapy. A therapy tested for melanoma, or skin cancer, involves
introducing a gene with an anticancer protein called tumor necrosis
factor (TNF) into test tube samples of the patient's own cancer cells,
which are then reintroduced into the patient. In brain cancer, the
approach is to insert a specific gene that increases the cancer cells'
susceptibility to a common drug used in fighting the disease. In
2003, researchers reported that they had harnessed the cell killing
properties of adenoviruses to treat prostate cancer. A 2004 report
said that researchers had developed a new DNA vaccine that
targeted the proteins expressed in cervical cancer cells.

Gaucher disease is an inherited disease caused by a mutant gene

that inhibits the production of an enzyme called glucocerebrosidase.
Patients with Gaucher disease have enlarged livers and spleens
and eventually their bones deteriorate. Clinical gene therapy trials
focus on inserting the gene for producing this enzyme.

Gene therapy also is being considered as an approach to solving a

problem associated with a surgical procedure known as
balloon angioplasty. In this procedure, a stent (in this case, a type
of tubular scaffolding) is used to open the clogged artery. However,
in response to the trauma of the stent insertion, the body initiates a
natural healing process that produces too many cells in the artery
and results in restenosis, or reclosing of the artery. The gene
therapy approach to preventing this unwanted side effect is to cover
the outside of the stents with a soluble gel. This gel contains vectors
for genes that reduce this overactive healing response.

Regularly throughout the past decade, and no doubt over future

years, scientists have and will come up with new possible ways
for gene therapy to help treat human disease. Recent
advancements include the possibility of reversing hearing loss in
humans with experimental growing of new sensory cells in adult
guinea pigs, and avoiding amputation in patients with severe
circulatory problems in their legs with angiogenic growth factors.

The Human Genome Project

Although great strides have been made in gene therapy in a
relatively short time, its potential usefulness has been limited by
lack of scientific data concerning the multitude of functions that
genes control in the human body. For instance, it is now known that
the vast majority of genetic material does not store information for
the creation of proteins, but rather is involved in the control and
regulation of gene expression, and is, thus, much more difficult to
interpret. Even so, each individual cell in the body carries thousands
of genes coding for proteins, with some estimates as high as
150,000 genes. For gene therapy to advance to its full potential,
scientists must discover the biological role of each of these
individual genes and where the base pairs that make them up are
located on DNA.

To address this issue, the National Institutes of Health initiated

the Human Genome Project in 1990. Led by James D. Watson (one
of the co-discoverers of the chemical makeup of DNA) the project's
15-year goal is to map the entire human genome (a combination of
the words gene and chromosomes). A genome map would clearly
identify the location of all genes as well as the more than three
billion base pairs that make them up. With a precise knowledge of
gene locations and functions, scientists may one day be able to
conquer or control diseases that have plagued humanity for
centuries.
Scientists participating in the Human Genome Project identified an
average of one new gene a day, but many expected this rate of
discovery to increase. By the year 2005, their goal was to determine
the exact location of all the genes on human DNA and the exact
sequence of the base pairs that make them up. Some of the genes
identified through this project include a gene that predisposes
people to obesity,one associated with programmed cell death
(apoptosis), a gene that guides HIV viral reproduction, and the
genes of inherited disorders like Huntington's disease, Lou Gehrig's
disease, and some colon and breast cancers. In April 2003, the
finished sequence was announced, with 99% of the human
genome's gene-containing regions mapped to an accuracy of
99.9%.

The future of gene therapy

Gene therapy seems elegantly simple in its concept: supply the
human body with a gene that can correct a biological malfunction
that causes a disease. However, there are many obstacles and
some distinct questions concerning the viability of gene therapy. For
example, viral vectors must be carefully controlled lest they infect
the patient with a viral disease. Some vectors, like retroviruses, also
can enter cells functioning properly and interfere with the natural
biological processes, possibly leading to other diseases. Other viral
vectors, like the adenoviruses, often are recognized and destroyed
by the immune system so their therapeutic effects are short-lived.
Maintaining gene expression so it performs its role properly after
vector delivery is difficult. As a result, some therapies need to be
repeated often to provide long-lasting benefits.

One of the most pressing issues, however, is gene regulation.

Genes work in concert to regulate their functioning. In other words,
several genes may play a part in turning other genes on and off. For
example, certain genes work together to stimulate cell division and
growth, but if these are not regulated, the inserted genes could
cause tumor formation and cancer. Another difficulty is learning how
to make the gene go into action only when needed. For the best and
safest therapeutic effort, a specific gene should turn on, for
example, when certain levels of a protein or enzyme are low and
must be replaced. But the gene also should remain dormant when
not needed to ensure it doesn't oversupply a substance and disturb
the body's delicate chemical makeup.

One approach to gene regulation is to attach other genes that

detect certain biological activities and then react as a type of
automatic off-and-on switch that regulates the activity of the other
genes according to biological cues. Although still in the rudimentary
stages, researchers are making headway in inhibiting some gene
functioning by using a synthetic DNA to block gene transcriptions
(the copying of genetic information). This approach may have
implications for gene therapy.

The ethics of gene therapy

While gene therapy holds promise as a revolutionary approach to
treating disease, ethical concerns over its use and ramifications
have been expressed by scientists and lay people alike. For
example, since much needs to be learned about how these genes
actually work and their long-term effect, is it ethical to test these
therapies on humans, where they could have a disastrous result?
As with most clinical trials concerning new therapies, including
many drugs, the patients participating in these studies usually have
not responded to more established therapies and often are so ill the
novel therapy is their only hope for long-term survival.
Another questionable outgrowth of gene therapy is that scientists
could possibly manipulate genes to genetically control traits in
human offspring that are not health related. For example, perhaps a
gene could be inserted to ensure that a child would not be bald, a
seemingly harmless goal. However, what if genetic manipulation
was used to alter skin color, prevent homosexuality, or ensure good
looks? If a gene is found that can enhance intelligence of children
who are not yet born, will everyone in society, the rich and the poor,
have access to the technology or will it be so expensive only the
elite can afford it?

The Human Genome Project, which plays such an integral role for
the future of gene therapy, also has social repercussions. If
individual genetic codes can be determined, will such information be
used against people? For example, will someone more susceptible
to a disease have to pay higher insurance premiums or be
denied health insurance altogether? Will employers discriminate
between two potential employees, one with a "healthy" genome and
the other with genetic abnormalities?

Some of these concerns can be traced back to the eugenics

movement popular in the first half of the twentieth century. This
genetic "philosophy" was a societal movement that encouraged
people with "positive" traits to reproduce while those with less
desirable traits were sanctioned from having children. Eugenics was
used to pass strict immigration laws in the United States, barring
less suitable people from entering the country lest they reduce the
quality of the country's collective gene pool. Probably the most
notorious example of eugenics in action was the rise of Nazism
in Germany, which resulted in the Eugenic Sterilization Law of 1933.
The law required sterilization for those suffering from certain
disabilities and even for some who were simply deemed "ugly." To
ensure that this novel science is not abused, many governments
have established organizations specifically for overseeing the
development of gene therapy. In the United States, the Food and
Drug Administration (FDA) and the National Institutes of Health
require scientists to take a precise series of steps and meet
stringent requirements before proceeding with clinical trials. As of
mid-2004, more than 300 companies were carrying out gene
medicine developments and 500 clinical trials were underway. How
to deliver the therapy is the key to unlocking many of
the researchers discoveries.

In fact, gene therapy has been immersed in more controversy and

surrounded by more scrutiny in both the health and ethical arena
than most other technologies (except, perhaps, for cloning) that
promise to substantially change society. Despite the health and
ethical questions surrounding gene therapy, the field will continue to
grow and is likely to change medicine faster than any previous
medical advancement.

KEY TERMS

Cell— The smallest living unit of the body that groups together to
form tissues and help the body perform specific functions.

Chromosome— A microscopic thread-like structure found within

each cell of the body, consisting of a complex of proteins and DNA.
Humans have 46 chromosomes arranged into 23 pairs. Changes in
either the total number of chromosomes or their shape and size
(structure) may lead to physical or mental abnormalities.

Clinical trial— The testing of a drug or some other type of therapy

in a specific population of patients.
Clone— A cell or organism derived through asexual (without sex)
reproduction containing the identical genetic information of the
parent cell or organism.

Deoxyribonucleic acid (DNA)— The genetic material in cells that

holds the inherited instructions for growth, development, and cellular
functioning.

Embryo— The earliest stage of development of a human infant,

usually used to refer to the first eight weeks of pregnancy. The
term fetus is used from roughly the third month of pregnancy until
delivery.

Enzyme— A protein that causes a biochemical reaction or change

without changing its own structure or function.

Eugenics— A social movement in which the population of a

society, country, or the world is to be improved by controlling the
passing on of hereditary information through mating.

Gene— A building block of inheritance, which contains the

instructions for the production of a particular protein, and is made up
of a molecular sequence found on a section of DNA. Each gene is
found on a precise location on a chromosome.

Gene transcription— The process by which genetic information is

copied from DNA to RNA, resulting in a specific protein formation.

Genetic engineering— The manipulation of genetic material to

produce specific results in an organism.

Genetics— The study of hereditary traits passed on through the

genes.
Germ-line gene therapy— The introduction of genes into
reproductive cells or embryos to correct inherited genetic defects
that can cause disease.

Liposome— Fat molecule made up of layers of lipids.

Macromolecules— A large molecule composed of thousands of

atoms.

Nitrogen— A gaseous element that makes up the base pairs in

DNA.

Nucleus— The central part of a cell that contains most of its genetic
material, including chromosomes and DNA.

Protein— Important building blocks of the body, composed of

amino acids, involved in the formation of body structures and
controlling the basic functions of the human body.

Somatic gene therapy— The introduction of genes into tissue or

cells to treat a genetic related disease in an individual.

Vectors— Something used to transport genetic information to a

cell.

Resources

PERIODICALS

Abella, Harold. "Gene Therapy May Save Limbs." Diagnostic

Imaging (May 1, 2003): 16.

Christensen R. "Cutaneous Gene Therapy—An

Update." Histochemical Cell Biology (January 2001): 73-82.
"Gene Therapy Important Part of Cancer Research." Cancer Gene
Therapy Week (June 30, 2003): 12.

"Initial Sequencing and Analysis of the Human

Genome." Nature (February 15, 2001): 860-921.

Kingsman, Alan. "Gene Therapy Moves On." SCRIP World

Pharmaceutical News (July 7, 2004): 19:ndash;21.

Nevin, Norman. "What Has Happened to Gene Therapy?" European

Journal of Pediatrics (2000): S240-S242.

"New DNA Vaccine Targets Proteins Expressed in Cervical Cancer

Cells." Gene Therapy Weekly(September 9, 2004): 14.

"New Research on the Progress of Gene Therapy Presented at

Meeting." Obesity, Fitness & Wellness Week (July 3, 2004): 405.

Pekkanen, John. "Genetics: Medicine's Amazing Leap." Readers

Digest (September 1991): 23-32.

Silverman, Jennifer, and Steve Perlstein. "Genome Project

Completed." Family Practice News (May 15, 2003): 50-51.

"Study Highlights Potential Danger of Gene Therapy." Drug

Week (June 20, 2003): 495.

"Study May Help Scientists Develop Safer Mthods for Gene

Therapy." AIDS Weekly (June 30, 2003): 32.

Trabis, J. "With Gene Therapy, Ears Grow New Sensory

Cells." Science News (June 7, 2003): 355.

ORGANIZATIONS
National Human Genome Research Institute. The National Institutes
of Health. 9000 Rockville Pike, Bethesda, MD 20892. (301) 496-
2433. 〈http://www.nhgri.nih.gov〉.

OTHER

Online Mendelian Inheritance in Man. Online genetic testing

information sponsored by National Center for Biotechnology
Information. 〈http://www.ncbi.nlm.nih.gov/Omim/〉.
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Gene Therapy
Genetics
Copyright Genetics Society of America

Gene Therapy

Gene therapy is a new and largely experimental branch of medicine

that uses genetic material (DNA) to treat patients. Researchers
hope one day to use this therapy to treat several different kinds of
diseases. While rapid progress has been made in this field in recent
years, very few patients have been successfully treated by gene
therapy, and a great deal of additional research remains to be done
to bring these techniques into common use.

Disease Targets
Humans possess two copies of most of their genes. In a recessive
genetic disease, both copies of a given gene are defective. Many
such illnesses are called loss-of-function genetic diseases, and they
represent the most straightforward application of gene therapy: If a
functional copy of the defective gene can be delivered to the correct
tissue and if it makes ("expresses") its normal protein there, the
patient could be cured. Other patients suffer from dominant genetic
diseases. In this case, the patient has one defective copy and one
normal copy of a given gene. Some of these disorders are called
gain-of-function diseases because the defective gene actively
disrupts the normal functioning of their cells and tissues (some
recessive diseases are also gain-of-function diseases). This
defective copy would have to be removed or inactivated in order to
cure these patients.

Gene therapy may also be effective in treating cancer or viral

infections such as HIV-AIDS. It can even be used to modify the
body's responses to injury. These approaches could be used to
reduce scarring after surgery or to reduce restenosis, which is the
reclosure of coronary arteries after balloon angioplasty. Each of
these cases will be discussed in more detail below, but first we will
deal with two technical issues of gene transfer: gene delivery and
longevity of gene expression.

Gene Delivery
Whether given as pills or injections, most conventional drugs simply
need to reach a minimal level in the bloodstream in order to be
effective. In gene therapy, the drug (DNA) must be delivered to the
nucleus of a cell in order to function, and a huge number of
individual cells must each receive the DNA in order for the treatment
to be effective. The situation is further complicated by the fact that a
given gene may normally function in only a small portion of the cells
in the body, and ectopic expression may be toxic. Thus,
successful gene therapy often requires highly efficient delivery of
DNA to a very restricted population of cells within the body.

To achieve these goals, many researchers have turned to viruses.

Viruses are parasites that normally reproduce by infecting individual
cells in the human body, delivering their DNA to the nucleus of
those cells. Once there, the viral DNA takes over the cell, converting
it to a factory to make more viruses. The cell eventually dies,
releasing more viruses to continue the cycle. Scientists can remove
or disable some of the genetic material of the virus, making it unable
to reproduce outside of the laboratory. This genetic material can
then be replaced by the gene needed to treat a patient. The
modified (or recombinant) virus can then be administered to the
patient, where it will carry the therapeutic gene into the target cells.
In this way, scientists can take advantage of the virus's ability,
gained over millions of years of evolution, to deliver DNA to cells
with tremendous efficiency. One of the most commonly used is a
cold virus called adenovirus. Recombinant adenoviruses have been
used in experimental gene therapy for muscle diseases, and can
deliver genes to almost all of the cells in a small region surrounding
the site of injection. Unfortunately, while adenoviruses excel at gene
delivery, evolution is a double-edged sword, and the many
mechanisms our own bodies have evolved to combat harmful viral
infections are also used against therapeutic viruses, as will be
discussed in more detail below.

Recombinant adenoviruses cannot be used to transfer DNA to all

cell types, because they cannot reproduce themselves outside of
the laboratory. When a cell with a recombinant adenovirus in it
divides, only one of the two resulting cells contains the virus and the
therapeutic gene it bears. The treatment of some diseases requires
gene transfer to a stem cell, a cell that actively divides to create
many new cells. For example, white blood cells live for only a short
time, and must be constantly replenished by the division
of precursor cells called hematopoietic stem cells. Gene therapy to
treat an immune disease affecting white blood cells would thus
require targeting these rapidly dividing cells. Researchers use a
different kind of virus to accomplish this: retroviruses, so called
because they contain RNA (a different kind of genetic material)
rather than DNA.

When a retrovirus infects a cell, it converts its RNA to DNA and

inserts it into the chromosome of the target cell. As the cell
subsequently copies its own DNA during cell division, it copies the
viral DNA as well, so that all of the progeny cells contain the
retroviral DNA. At some later time, the viral DNA can liberate itself
from the chromosome, direct the manufacture of many new viruses,
and go on to repeat its life cycle. Recombinant retro-viruses are
engineered so that they can enter the target cell's chromosome, but
become trapped there, unable to liberate themselves and continue
their life cycle. Because all progeny cells still carry the recombinant
retrovirus, they will also carry the therapeutic gene.

This is a great advantage over adenoviruses as a tool for gene

delivery to dividing cells, but retroviruses have some drawbacks as
well. They can only infect cells that are dividing quickly, and in most
cases this infection must be carried out in the laboratory. Cells must
be removed from the patient, infected with the recombinant
retrovirus, grown for several weeks in the lab, and then reintroduced
to the patient's body. This process, called ex vivo gene transfer, is
extremely expensive and labor intensive. Nonetheless, this form
of gene therapy has been used in one of the most successful
clinical applications to date, the treatment of two patients with
severe combined immune deficiency (SCID) caused by a defect in
the adenosine deaminase gene.

Before treatment, these patients had essentially no immune system

at all, and would have been required to live as "bubble children,"
completely isolated in a sterile environment. While their treatment
did not completely cure their genetic disorder, it restored their
immune systems enough to allow them to leave their sterile isolation
chambers and live essentially normal lives. Many other viruses are
being engineered for application to gene delivery, including adeno-
associated virus, herpes simplex virus, and even extensively
modified forms of the human immunodeficiency virus (HIV), to name
just a few.

Many researchers are also exploring nonviral methods for gene

delivery. One of the most successful of these methods consists of
coating the therapeutic DNA with specialized fat molecules called
lipids. The resulting small fatty drops called vesicles can then be
injected or inhaled to deliver the DNA to the target tissue. Many
different lipid formulations have been tested and different
formulations work better in different tissues. These approaches
have the great advantage that they do not stimulate the serious
immune response that some viral vectors do. However, in general,
these nonviral methods are not as efficient as viruses at transferring
DNA to the target cells. No clearly superior method for gene delivery
has yet emerged, and scientists are still actively developing both
viral and nonviral methods. It is likely that many different methods
will eventually be used, with each method specifically tailored to
work best in a specific tissue or organ of the body.

Longevity of Gene Expression

One of the most challenging problems in gene therapy is to achieve
long-lasting expression of the therapeutic gene, also called the
transgene. Often the virus used to deliver the transgene causes the
patient's body to produce an immune response that destroys the
very cells that have been treated. This is especially true when an
adenovirus is used to deliver genes. The human body raises a
potent immune response to prevent or limit infections by
adenovirus, completely clearing it from the body within several
weeks. This immune response is frequently directed at proteins
made by the adenovirus itself.

To combat this problem, researchers have deleted more and more

of the virus's own genetic material. These modifications make the
viruses safer and less likely to raise an immune response, but also
make them more and more difficult to grow in the quantities
necessary for use in the clinic. Expression of therapeutic transgenes
can also be lost when the regulatory sequences that control a gene
and turn it on and off (called promoters and enhancers) are shut
down. Although inflammation has been found to play a role in this
process, it is not well understood, and much
additional research remains to be done.

Examples of Gene Therapy Applications

There are many conditions that must be met in order to allow gene
therapy to be possible. First, the details of the disease process must
be understood. Of course, scientists must know exactly what gene
is defective, but also when and at what level that gene would
normally be expressed, how it functions, and what the regenerative
possibilities are for the affected tissue. Not all diseases can be
treated by gene therapy. It must be clear that replacement of the
defective gene would benefit the patient. For example, a mutation
that leads to a birth defect might be impossible to treat, because
irreversible damage will have already occurred by the time the
patient is identified. Similarly, diseases that cause death of brain
cells are not well suited to gene therapy: Although gene
therapy might be able to halt further progression of disease, existing
damage cannot be reversed because brain cells cannot regenerate.
Additionally, the cells to which DNA needs to be delivered must be
accessible. Finally, great caution is warranted as gene therapy is
pursued, as the body's response to high doses of viral vectors can
be unpredictable. On September 12, 1999, Jesse Gelsinger, an
eighteen-yearold participant in a clinical trial in Philadelphia,
became unexpectedly ill and died from side effects of liver
administration of adenovirus. This tragedy illustrates the importance
of careful attention to safety regulations and extensive experiments
in animal model systems before moving to human clinical trials.

Muscular Dystrophies.

Duchenne and other recessive muscular dystrophies are well suited

in many ways for gene therapy. These are loss-of-function
recessive genetic diseases caused by mutations in the dystrophin
gene or in genes for other structural muscle proteins. The normal
levels of these proteins are known, as are many of the ways that
they function in the muscle cell. There is ample evidence in animal
model systems that these diseases can be cured by delivery of
functional copies of the gene. This is true in large part because
muscle tissue has a tremendous capacity for repair and
regeneration, so one could imagine that the heavily damaged
muscle could repair itself after successful gene transfer. Muscle
tissue is also an excellent target for gene transfer.

Several different approaches have been used to transfer DNA to

muscle. The most straightforward approach is the direct
intramuscular injection of DNA in a circular form called a plasmid .
The advantage to this approach is that it induces little to no immune
response, although the overall number of cells expressing the gene
is fairly low. In contrast, recombinant adenoviruses are extremely
efficient at transferring genes to muscle, but give rise to a potent
immune response that results in only short-term expression of the
transferred genes. Because the efficiency of adenoviral transfer is
so great, huge efforts are underway to reduce
the immunogenicity of these vectors. These efforts have produced
some significantly improved vectors, and research is now focusing
on developing methods to prepare the large quantities necessary for
clinical use. Adeno-associated virus combines the extremely high
efficiency of adenoviral transfer with the very low immunogenicity of
direct DNA transfer. However, this virus has a rather small capacity
to carry DNA, so small that it cannot carry the dystrophin gene (one
of the largest genes known), which is needed to treat
Duchenne muscular dystrophy.

From these examples, it should be clear that many different

approaches to gene therapy for muscular dystrophy have been
tried, but that each approach suffers from one or more key
shortcomings. In addition, all of these approaches to treat muscular
dystrophy face one common problem: Although it is easy to transfer
genes to a small part of a single muscle, simultaneously delivering a
gene to all parts of all the muscles of the body is impossible with
today's technology.

Hemophilia and Sickle Cell Disease.

Because of the difficulty in treating diseases such as muscular

dystrophy, many researchers have chosen to focus on genetic
diseases that may be easier to treat, particularly those resulting
from the lack of proteins freely dissolved in the bloodstream.
Hemophilia is one such disorder, caused by a lack of blood-clotting
proteins. Such patients have long been treated by the infusion of the
missing clotting proteins, but this treatment is extremely expensive
and requires almost daily injections. Gene therapy holds great
promise for these patients, because replacement of the gene that
makes the missing protein could permanently eliminate the need for
protein injections. It really does not matter what tissue produces
these clotting factors as long as the protein is delivered to the
bloodstream, so researchers have tried to deliver these genes to
muscle and to the liver using several different vectors. Approaches
using recombinant adenoviruses to deliver the clotting factor gene
to the liver are especially promising, and tests have shown
significant clinical improvement in a dog model of hemophilia.

Gain-of-function genetic diseases present a very different sort of

challenge because the mutant gene or genes create a new
biological activity that actively interferes with the normal functioning
of the cell. An example of such a disorder is sickle cell disease.
Patients suffering from this disease have a defective hemoglobin
protein in their red blood cells. This defective protein can cause their
red blood cells to be misshapen, clogging their blood vessels and
causing extremely painful and dangerous blood clots. Most of our
genes make an RNA transcript, which is then used as a blueprint to
make protein. In sickle cell disease, the transcript of the mutant
gene needs to be destroyed or repaired in order to prevent the
synthesis of mutant hemoglobin.

The molecular repair of these transcripts is possible using special

RNA molecules called ribozymes . There are several different kinds
of ribozymes: some that destroy their targets, and others that modify
and repair their target transcripts. The repair approach was tested in
the laboratory on cells containing the sickle cell mutation, and was
quite successful, repairing a significant fraction of the mutant
transcripts. While patients cannot yet be treated using this
technique, the approach illustrates how biologically damaging
molecules can be inactivated. Similar approaches are being
developed to treat HIV-AIDS infections, and these may one day be
used along with other antiviral therapies to treat this dreaded
disease.

Cancer.

Very different strategies of gene therapy are used to treat cancer.

When treating diseases such as muscular dystrophy, researchers
try to deliver genes without detection by the patient's immune
system. When treating cancer, the object is often precisely the
opposite: to stimulate a patient's immune reaction to the tumor
tissue and improve its ability to fight the disease. For this reason,
tumor tissue is often transformed by the new gene to produce
specific activators of the immune system, such as interleukins or
GM-CSF (granulocyte monocyte colony stimulating factor).

Usually, cancer cells are not recognized by the immune system

because they are in many ways identical to the patient's normal
cells. These stimulating factors activate the immune system and
help it recognize and attack the tumor tissue. In another approach,
called "suicide therapy," a gene such as the herpes simplex virus
thymidine kinase gene (HSV-TK ) is transferred to the tumor. This
gene normally does not occur in the human body, and it is not
metabolically active. After several rounds of gene therapy have built
up high levels of TK activity in the tumor, a drug called ganciclovir is
given to the patient. This drug is inactive in normal cells, but the TK
gene converts it into a potent toxin, killing the tumor cells. Even
nearby tumor cells that do not have the TK gene can be killed by a
phenomenon called the "bystander effect." This approach not only
kills tumor cells directly, but also activates the immune system to
further attack the tumor.
Anticancer gene therapy is a powerful adjunct to other more
traditional forms of cancer treatment. Its advantages are that it can
be beneficial even if only a portion of the tumor cells receive the
transferred gene, there is no need for long-term gene expression,
and it works with the immune system, rather than trying to defeat it.
Anticancer gene therapy is already in significant use in the clinic,
and is likely to become even more commonplace in the near future.

In summary, gene therapy covers several related areas

of research and clinical treatment, all using the genetic material
DNA as a drug. Gene therapy is currently being used, along with
other techniques, to treat cancer. One day, gene therapy may also
be used to treat a variety of hereditary and nonhereditary diseases,
ranging from loss-of-function disorders such as muscular dystrophy
and hemophilia, to gain-of-function disorders such as sickle cell
disease, to viral diseases such as HIV-AIDS. Active areas
of research include improvements in the methods of gene delivery
to the individual tissues and cells of the body and the modulation of
the immune response to gene delivery. Many challenges remain to
the successful maturation of gene therapy from the laboratory to the
clinical setting.

See also Cancer; Cystic Fibrosis; Disease, Genetics of; Embryonic

Stem Cells; Gene Discovery; Gene Therapy: Ethical Issues;
Hemophilia; Muscular Dystrophy; Retrovirus; Ribozyme; Severe
Combined Immune Deficiency; Virus.

Michael A. Hauser

Bibliography

Beardsley, T. "Working under Pressure." Scientific American 282

(2000): 34.
Clark, William R. The New Healers: The Promise and Problems of
Molecular Medicine in the Twenty-first Century. New York: Oxford
University Press, 1999.

Vogel, G. "Gene Therapy: FDA Moves against Penn

Scientist." Science 290 (2000):2049-2051.
Internet Resource

Institute for Human Gene Therapy.

<http://www.yshs.upenn.edu/ihgt/>.

In April 2002 researchers announced that ex vivo gene therapy for

severe combined immunodeficiency had been successful in five
boys for up to 2.5 years.
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Gene Therapy
Gale Encyclopedia of Neurological Disorders
COPYRIGHT 2005 The Gale Group, Inc.

Gene therapy

Definition
Classic gene therapy is the direct use of genetic material in the
treatment of disease. This usually involves inserting a functional
gene or DNA fragment into key cells to mitigate, or cure, a disease.
A broader definition of gene therapy includes all applications of DNA
technology to treat disease. For people with certain neurological
conditions such as Parkinson's disease and Canavan disease ,
initial gene therapy trials have shown promise. Developing gene
therapies for treating disorders of the nervous system poses unique
challenges, such as how to introduce the therapeutic gene across
the blood-brain barrier or how to target the therapeutic gene to one
specific area of the brain.

Purpose
Genes play a role in every function of the human body. Defects or
mutations within a gene can lead to malfunction or disease of cells,
tissues, and/or organs. Although standard drug therapy is usually
effective in treating the symptoms of a disorder, a patient may be
required to take the drugs for an extended time and there may be
serious or unpleasant side effects. However, a patient may be cured
with few negative consequences if treatment can be targeted
directly at the specific cause of the disease (the gene defect), or if
that cause can be neutralized or reversed. Therefore, gene
therapy provides an attractive alternative to drug therapy as it seeks
to provide treatment strategies that will be more complete and less
toxic to the patient. Furthermore, gene therapy may provide a way
of treating diseases that cannot be managed by standard therapies.

Description
There are many diverse approaches to gene therapy since the
biological basis of each disease is unique, presenting a different set
of parameters and challenges. However, in each case, a basic set
of criteria must be met. First, it is essential to fully understand the
disease to be treated. The cells or tissues associated with the
disease must be well defined and accessible. The gene and the
specific mutation or mutations causing the disease must be known,
and it must be possible to isolate or synthesize a normal, functional
copy of that gene and to incorporate it into a vector. The vector then
transfers the new gene to the target cells where, hopefully, the gene
will become fully active. The most common roles for the expressed
gene include replacing a defective gene, inhibiting or degrading a
deleterious DNA, RNA, or protein, or directly or indirectly killing the
cell.

Single gene disorders resulting in a loss of gene function in one

specific target tissue provide the easiest options for gene therapy,
though strategies for many types of mutations have been
investigated. A broad spectrum of diseases has been considered
for gene therapy, including:
 neurological disorders, e.g., Parkinson disease, Huntington disease
 muscular dystrophies
 immunological disorders, e.g., severe combined immunodeficiency syndrome
(SCIDS)
 blood abnormalities, e.g., thalassemias, hemophilia
 cancer

Unfortunately, many of the more commonly occurring disorders,

including heart disease, diabetes, and high blood pressure, result
from defects in multiple genes making them unlikely candidates
for gene therapy using existing technologies.

For each disease, it must be determined if ex vivo or in

vitro technology is the best approach. In ex vivotechnology, patient
cell samples are collected and cultured in the laboratory. The new
gene is incorporated into the growing cells, and these are
subsequently transferred back into the patient. Not all of the
cultured cells will include the new gene, and not all will survive the
transfer. The hope is that a sufficient number of the modified cells
will be functional in the patient such that the therapy will reverse the
disease. In vitro therapy involves injecting the new gene directly into
the target tissue where the individual cells must pick it up. Of the
two, this method is technically easier and cheaper, but it is harder to
determine how many of the target cells actually acquire the new
gene. Ex vivo therapy is more expensive and time consuming, but
allows greater control of the conditions.

Both processes require the use of a vector to get the new gene
across the cell membrane and into a cell. Viruses have proven to be
highly effective as vectors since these are biological entities with a
natural function of infecting host cells. DNA technology allows
viruses to be manipulated to replace the normal payload of disease-
causing genetic material with therapeutic genes. The virus will retain
its ability to infect a host cell but, instead of causing a disease, it will
deposit the new gene into the cell.

Other mechanisms of gene transfer have also been investigated.

Artificial chromosomes have been developed, but these are often
too large to move across cell membranes. Liposomes, structures
with lipid membranes, that encompass genetic material can be
successfully used as vectors if the liposome is absorbed by the cell
or if its membrane fuses with the cell membrane releasing the new
gene inside the cell.

Once the gene enters the cell, one of two things occurs. It may be
degraded and lost, which is an unfavorable outcome. Preferably, the
gene will stably incorporate into the DNA of the target cell so that it
can be processed as a normal part of that genome. If the gene
therapy is designed to replace a defective gene, the best-case
scenario is for the new gene to integrate into a completely
renewable cell such as a stem cell. Theoretically, in this situation,
the gene will be permanently incorporated into the patient's body
and no further therapy will be required. Alternatively, if the gene
integrates into a genome of a cell with a finite lifespan, the beneficial
effects of the gene will only exist while that cell lives, requiring
the gene therapy to be repeated at a later time.

One of the early successes of gene therapy was for a four-year-old

girl with adenine deaminase (ADA) deficiency. This is a form of
SCIDS that results in malfunction of the immune system and can
lead to death as a result of severe infection. Conventional treatment
had failed for this patient, making her a candidate for gene therapy.
A normal ADA gene was incorporated into a retroviral vector that
transferred the gene into the patient's lymphocytes in vitro. The
modified cells were returned to her circulation by transfusion. After
five months, her levels of ADA activity had risen from less than 1%
to 50%. With additional therapies over the next two years, her
health improved as the enzyme activity stabilized, and she was able
to begin a normal life. Twelve years later, she still demonstrates
reasonable levels of ADA activity, but the gene therapy was not a
cure as she must continue to receive the standard enzyme
replacement therapy to maintain her health.

Acquired diseases can also be treated with gene therapy as

demonstrated by a novel strategy for treating brain cancer. The
thymidine kinase (TK) gene from the herpes simplex virus (HSV)
has an enzymatic property that converts the drug ganciclovir into a
toxic substance that can kill human cells. It was postulated that this
could be used as a targeted killing tool. To investigate, cloned HSV
TK genes were injected into brain tumors. In the brain, only the
tumor cells are dividing, so these are the only cells that will be
infected by the viral vector, and are thus the only cells that will
receive the HSV TK gene. When the patient is subsequently treated
with ganciclovir, the tumor cells that have incorporated the HSV TK
gene will be selectively killed. Clinical trials proved that tumor cells
could be selectively eliminated by demonstrating a reduction in the
size of the brain tumors in seven of nine patients.

A completely different set of therapies is possible if the idea of gene

therapy includes the use of DNA for patient treatment in ways other
than inserting new genes into cells. One example is the drug
Gleevec that was approved in 2001 for use in patients with chronic
myelogenous leukemia (CML). Gleevec is a substance that binds to
the defective protein produced in CML, blocking that protein's
activity and alleviating the symptoms of the disease. This is a
targeted therapy that affects only the cells with the CML mutation,
so there are very few side effects. Recombinant DNA technology
has also been utilized to generate genetically engineered copies of
vaccines (Recombivax HB), antibodies, and normal gene products
(insulin).

Aftercare
If the new DNA can be stably incorporated into the proper
regenerative target cells, the patient may be cured of disease. No
additional care should be required, although periodic monitoring of
the patient is appropriate.

For gene therapies in which the new DNA is inserted into cells with
a finite lifespan, the therapeutic effect will be lost when those cells
die. In these situations, the patient will require continuing
treatments. Monitoring of patients who receive drugs and
substances arising from recombinant DNA technology is the same
as standard drug therapy.

Precautions
Currently classic gene therapy is still experimental. Although many
patients have shown significant improvement following their
treatment, at least two individuals have died as a result of this type
of therapy. Therefore, experts carefully review all protocols before
any studies are undertaken. Initial research is done in an animal
model system, and any problems detected are carefully evaluated
before the same treatments are attempted in humans.

Risks
A patient who is receiving gene therapy may face a number of
potential problems. The viral vectors used may cause infection
and/or inflammation of tissues, and artificial introduction of viruses
into the body may initiate other disease processes. Functional gene
therapy relies on stable incorporation of a new gene into an
individual's own DNA. As the integration is random, occasionally the
new gene may insert within another normally functioning gene,
causing its damage or inactivation. This, in turn, could lead to
cancer or other disease. It is also critical that the new gene have the
proper regulatory controls so that the gene product is produced in
the proper amount. Over-expression of certain genes can have
deleterious results. Any of these problems could render the gene
therapy ineffective, or, at worst, cause the death of the subject.

Normal results
Classic gene therapy seeks to treat or cure a defined disease by
incorporating a functional gene or gene product into target cells of
an affected individual.

Resources

BOOKS
George, Linda. Gene Therapy. Woodbridge, CT: Blackbirch
Marketing, 2003.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F.

Willard. Thompson and Thompson Genetics in Medicine, 6th
edition. Philadelphia, PA: W. B. Saunders Company, 2001.

Strachan, T., and Andrew P. Read. Human Molecular Genetics, 2nd

edition. New York, NY: John Wiley and Sons, 1999.

OTHER

National Cancer Institute. Questions and Answers about Gene

Therapy. Cited January 4, 2004 (March 23, 2004).
<http://cis.nci.nih.gov/fact/7_18.htm>.

Constance K. Stein
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Gene Therapy
Encyclopedia of Science and Religion
COPYRIGHT 2003 The Gale Group Inc.
Gene Therapy

Gene therapy refers to the repairing or replacing of malfunctioning

genes that cause a deleterious illness or condition. There are two
forms of gene therapy: somatic and germline.

Somatic and germline therapies

Somatic therapies are used to replace or repair malfunctioning
genes that are expressed in such conditions as cystic
fibrosis or sickle cell disease. Since these therapies attempt to
remedy the causes rather than alleviate the effects of disease, they
presumably will provide more effective and beneficial medical
treatments. Although initial attempts to develop somatic gene
therapies proved largely unsuccessful, experimental treatments
since the mid 1990s of severe combined immunodeficiency disease
(SCID) and sickle cell disease have renewed public optimism
regarding its potential efficacy.

Like somatic therapies, germline therapies attempt to repair or

replace malfunctioning genes. The principal difference is that the
corrected gene, rather than the deleterious one, is passed-on to
subsequent generations. Consequently, the potential benefits or
effects of germline therapies could be much more widespread than
those of somatic therapies. As of 2002, no experimental procedures
employing human germline techniques had been undertaken.

Ethical and moral objections

In principle, somatic gene therapy has raised few ethical objections.
Because these therapies treat the underlying causes of disease at
the molecular level rather than concentrating on affected organs or
compromised biological processes, somatic therapies have been
largely perceived as more sophisticated and potentially more
effective extensions of established medical procedures. So long as
these therapies are safe, there is nothing inherently wrong in
deploying them. The issue of safety, however, came to the forefront
with the death in 1999 of a patient undergoing an experimental
genetic treatment for ornithine transcarbamylase (OTC) deficiency,
an incident that prompted calls for greater public oversight or
regulation.

The prospect of germline therapy has proven much more

controversial. The primary objection is that humans should not
attempt to construct the genetic inheritance of future generations.
This objection usually takes one of two forms. First, since so little is
known about the complex relationship between genes and larger
environmental factors, it would be imprudent to introduce genetic
alterations that would be inherited by future generations. Although
the goal would be to eliminate a severely debilitating disease or
condition, there might be unintended or unforeseen consequences
that would adversely affect subsequent generations. Individuals
carrying a recessive deleterious gene, for example, might in the
future incur certain survival advantages in response to changing
environmental factors. Since the effects of germline therapy are so
much more widespread than those of somatic therapies, large
populations could be potentially devastated. The seemingly
harmless or even beneficial intervention into the human germline
could wreak havoc down the road.

The second form of this objection invokes a more sweeping moral

imperative. Humans do not have a right to shape the genetic
endowment of their descendants, and correspondingly, individuals
have the right to be born with unaltered genomes. People must
simply resist the temptation to play God in shaping the destiny of
humans, both as individuals and as a species.
The principal defense against this objection, in both its forms, is that
it does not sufficiently take into account the nature of evolutionary
change, thereby imposing unwarranted responsibilities regarding
the possible fate of future generations. Other than identical twins,
there are no unique genomes that parents do not have a right to
alter or that offspring have a right to inherit in an unaltered form.
Human reproduction entails the creation of a unique genome,
derived from the genes of parents but also including mutations. It is
difficult to imagine what an unaltered genome might be in the future
in evolutionary terms. If individuals have a right to inherit an
unaltered genome, then presumably cloning should become the
preferred method of human reproduction. In addition, many argue
that the prudential claim that current ignorance should prohibit
germline interventions is unwarranted. Every action entails
unforeseen consequences, and it is not known whether failing to
intervene will prove better or worse than intervening. It cannot be
known in advance whether the consequences of germline therapies
will be any more or less devastating than those of natural
selection upon future generations.

Some religious and moral concerns have also been raised, not so
much with the prospect of genetic therapy per se, but with the fear
that their introduction might exacerbate some already troubling
trends. For instance, it is argued that the growing knowledge of
human genetics is not being used, at least initially, to develop more
effective therapies, but to prevent the birth of offspring with
debilitating or undesirable genetic traits. Some fear that parents will
turn increasingly to embryonic testing and screening techniques,
such as preimplantation genetic diagnosis, to prevent the
implantation of embryos carrying certain genetic abnormalities,
leading in turn to the destruction of embryos deemed to be
undesirable.
The issue is further compounded because the same techniques
being developed as therapies may also be applied to select, and
perhaps someday enhance, certain genetic characteristics of
offspring. The bar of parental expectation would then be raised
dramatically regarding what constitutes a desirable or even healthy
child. The prospect of so-called designer babies will exert social
pressure on parents not only to prevent the birth of offspring with
severely debilitating conditions, but to select or enhance their
genetic endowment in the hope of giving their children the best
possible start in life. Although the development of genetic therapy is
motivated by a humane impulse, its advent could fuel parental
anxieties and prejudicial attitudes toward individuals with physical
and mental disabilities, thereby unwittingly supporting a new,
implicit, and insidious form of eugenics.

Proponents of genetic therapy counter that these worries are both

unfounded and inflammatory. Legal protections against
discrimination can be enacted as needed. Moreover, the best way
prevent the destruction of so-called undesirable embryos is to
develop effective genetic therapies as quickly as possible. More
importantly, the distinction between genetic therapy and genetic
selection and enhancement is spurious. Any therapy is also an
enhancement, because the restoration of health is presumably an
improvement over illness. In addition, many non-genetic medical
procedures are enhancing, rather than therapeutic, in character,
and genetic therapies will make them more effective. Genetically
enhancing an individual's immune system, for example, is merely a
more effective form of inoculation. Despite the moral and religious
objections, the development of effective gene therapies may
alleviate the suffering of many people.

See also Biotechnology; DNA; Ethnicity; Eugenics; Evolution; Gene

Therapy; Genetic Engineering; Genetic Testing; Genetically
Modified Organisms; Genetics; Human Genome Project; Mutation;
Nature versus Nurture; Playing God; Reproductive Technology

Bibliography
Chapman, audrey r. unprecedented choices: religious ethics at the
frontiers of genetic science. minneapolis, minn.: fortress press,
1999.

Engelhardt, h. tristram, jr. the foundations of bioethics. new york and

oxford: oxford university press, 1996.

Fletcher, joseph. the ethics of genetic control: ending reproductive

roulette. garden city, n.y.: anchor books, 1974.

Parens, eric, ed. enhancing human traits: ethical and social

implications. washington d.c.: georgetown university press, 1998.

Peterson, james c. genetic turning points: the ethics of human

genetic intervention. grand rapids, mich.: eerdmans, 2000.

Ramsey, paul. fabricated man: the ethics of genetic control. london

and new haven, conn.: yale university press. 1970.

Walters, leroy, and palmer, julie page. the ethics of human gene
therapy. new york: oxford university press, 1997.

Brent waters
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Gene Therapy
Medical Discoveries
COPYRIGHT 1997 Thomson Gale

Gene therapy

Gene therapy is a new field in which normal genes are given to

patients to cure genetic disorders. Some successes have occurred,
as well as some failures. But researchers believe that gene
therapy shows promise, because this approach to disease treats the
root of the disease instead of just its symptoms.

Three Types of Therapy

Three types of therapy currently exist. In gene replacement therapy,
a mutant gene is replaced with a normal gene. In gene
augmentation therapy, a normal gene is added but the mutant gene
is not removed. And in gene inactivation therapy, a gene is added
that will cancel the effects of the defective gene. Sometimes
combined to produce the desired cure, the type or types of therapy
selected depend on many factors, including whether the actual
genetic defect can be pinpointed exactly.

Body Must Be Tricked to Accept Cloned Genes

The point of gene therapy is twofold. First, the gene must be cloned
(created), or engineered. This process is also known as
recombinant DNA technology (first performed in 1972). Secondly,
the normal gene must be introduced into the patient's
chromosomes. The body, hoever, actually regards the cloned
"normal" gene as foreign, so the it must be tricked into accepting the
cure.

Of the various methods tried, the most efficient technique uses an

RNA virus called a retrovirus. The retrovirus infects the patient's
cells, then copies its DNA into the patient's DNA.

The first human gene therapy was approved for clinical trial in
the United States in May 1989. At the end of 1992, at least 37 gene
therapy projects were completed, in progress, or approved
in China, France, Italy, the Netherlands, and the United States.
Each country has its own approval process, designed to protect the
patient, the health workers, and the public. By mid-1995
the National Institutes of Health (NIH) and
Pharmaceutical Research and Manufacturers of America reported
increased efforts in this field. U.S. companies had
57 projects underway, 12 projects completed, and 18 pending, while
drug companies had 17 therapies in development.

In the United States, each procedure must be approved by the

director of the NIH, by the NIH Recombinant DNA Advisory
Committee, and by the U.S. Food and Drug Administration (FDA).

Therapy Trials
Gene therapy trials have included severe combined
immunodeficiency (SCID) and malignant melanoma. SCID is a rare
disease that prevents the person's immune system from functioning.
This well-publicized study concerned the teenager named David
who lived for several years in a plastic bubble to protect him from
infection.

Some cases of SCID result from ADA deficiency, a genetic mutation

that prevents lymphocytes from producing the enzyme adenosine
deaminase (ADA). Lymphocytes are white, or nearly colorless, cells
in the blood and lymph systems produced either by the bone
marrow (B cells) or by the thymus (T cells). T cell lymphocytes are
the major players in the body's immune system, which does not
develop normally without the enzyme ADA.

In September 1990 NIH researchers R. Michael Blaese and W.

French Anderson performed the world's first gene therapy on a four-
year-old child with SCID. A normal gene for ADA was inserted into a
virus and allowed to "infect" lymphocytes that had been withdrawn
from the child's body. Then the girl was injected with the altered
cells. During the next 18 months, the patient had several series of
injections, along with other treatment. A second patient, a nine-year-
old girl, had similar treatments. The cells encouraged production of
ADA in both children, who attended school, had only the normal
number of infections, and reportedly experienced no side effects.
Since then similar treatments have been used on children in other
countries.

Many gene therapy studies have been completed or are underway

for various cancers. In a study of the skin cancer melanoma,
doctors withdrew a sample of the patient's own cells, inserted an
altered gene, and returned the new cells to the patient. The purpose
of this procedure is to introduce a protein that will kill the melanoma
tumor.

Cystic Fibrosis Study Yields Few Results

A gene therapy study for the lung disease cystic fibrosis began in
1992. The therapy calls for inserting a needed gene into an
engineered cold virus (the virus is altered so that it will not cause a
cold), which the patients inhale. The gene enters the lung and
improves cell function, preventing the production of the mucus (a
slimy secretion) that blocks a patient's breathing.

The genes performed precisely under laboratory conditions, but in

human studies, less than one percent of patients achieved the
desired results. The results are not considered to be sufficient
enough to be promising.

Further Research
Another study concerned familial hypercholesterolemia, a condition
in which patients lack a gene for disposing of harmful low-density
lipoprotein cholesterol (the so-called "bad" cholesterol). These
patients develop a build-up of this low-density cholesterol in their
bodies. People lacking both copies of the gene usually die from
a heart attack in their early teens. Some-one with only one copy
suffers from severe coronary (heart) disease. Scientists at several
medical centers are studying insertion of the needed gene into cells
from a patient's liver, then injecting the cells into the person's body.

Scientists in China are studying the bleeding disease hemophilia B,

which occurs in people whose blood lacks clotting Factor
IX. Researchers are attempting to engineer cells with this factor.
Studies are also underway on gene therapy for AIDS, liver failure,
leukemia, brain tumor, various cancers, rheumatoid arthritis,
Gaucher's disease (a metabolic disorder), and various other
inherited diseases.

[See also Cloning ; Enzyme ; Gene ; Genetic Engineering ]

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Gene Therapy
The Oxford Companion to the Body
© The Oxford Companion to the Body 2001, originally published by Oxford University Press
2001.

Gene therapy is the treatment of human disease by gene transfer.

Many, or maybe most, diseases have a genetic component —
asthma, cancer, Alzheimer's disease, for example. However, most
diseases are polygenic, i.e. a subtle interplay of many genes
determines the likelihood of developing a disease condition,
whereas, so far, gene therapy can only be contemplated
for monogenic diseases, in which there is a single gene defect.
Even in these cases only treatment of recessive diseases can be
considered, where the correct gene is added in the continued
presence of the faulty one. Dominant mutations cannot be
approached in this way, as it would be necessary to knock out the
existing faulty genes in the cells where they are expressed (i.e.
where their presence shows an effect), as well as adding the correct
genetic information.

Gene therapy for recessive monogenic diseases involves

introducing correct genetic material into the patient. This can be
approached in two different ways. Cells can be taken from the
patient, modified in the laboratory (‘in vitro’), and then re-introduced,
or a carrier (‘vector’) of the correct genetic material can be delivered
directly into the patient. Examples are adenosine deaminase (ADA)
deficiency and cystic fibrosis, respectively.

ADA deficiency is a lethal monogenic disease in which adenosine is

not normally metabolized, leading to high levels of 2′-
deoxyadenosine, which is selectively toxic to cells of the immune
system (T and B cells) and leads to immunodeficiency. The gene
therapy for this disease is to isolate T cells from patients and treat
these cells in vitro with a retroviral vector — a virus, normally
capable of causing disease, which has been modified to carry the
required genetic information. Cells that have incorporated the new
genetic information into their genomes are selected and reinfused
back into the patient, allowing the appropriate metabolism of
adenosine to occur.

Cystic fibrosis (CF) is also a lethal disease resulting from a single

gene mutation. It disables normal cell membrane function. The gene
codes for a protein, the cystic fibrosis ‘transmembrane conductance
regulator’ (CFTR), which acts as a chloride ion channel in
the epithelia of the airways, alimentary canal, and numerous other
hollow organs. The correct genetic sequence can be incorporated
into a type of virus which ordinarily can infect the respiratory tract
(adenoviruses), or into genetic particles (plasmids) linked to lipids to
form lipocomplexes. Either of these can be delivered directly into
the patient's lungs.

Both the examples given must still be regarded as at the

experimental stage. In ADA deficiency the transformed T cells
persist for only 6 months, while in CF the new genetic material is not
incorporated into the genome and is expressed outside of it
(episomally) for only a few weeks. The major problems with gene
therapy relate to the delivery of new genetic instructions to the
appropriate body targets. Ideally, delivery should be to stem cells —
the progenitor cells which give rise to replacement cells as adult,
mature cells die. Furthermore, the material should be incorporated
into the genome so that all future generations of cells carry the
correct instructions. Retroviral vectors (viruses carrying the genetic
material) are incorporated in the genome, but this can only be used
in the in vitro type of procedure, when the treated cells are outside
the body. Incorporation of the new material into an inappropriate
position may switch on an oncogene which can lead to tumour
formation. Thus it is very necessary to be sure that cells
transformed in vitro behave normally before reintroducing them to
the patient. These problems do not occur with adenoviral vectors,
but expression persists for only a short time, thus requiring repeated
administration, leading to immune reactions. Use of lipoplexes
avoids this latter problem, but the efficiency of gene delivery by this
route is very low.

Gene therapy will undoubtedly have much to offer for the future.
Unlike many conventional therapies, it aims to cure disease rather
than simply treat the symptoms. The principles of gene therapy are
established, but technical problems, primarily related to efficient and
safe ways of delivery, have still to be overcome.

Alan W. Cuthbert
See also genetics, human; immune system.

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Gene Therapy
Biology
COPYRIGHT 2002 The Gale Group Inc.

Gene Therapy

Gene therapy is an experimental disease treatment in which a gene

is delivered to cells in the body. The protein made by the new gene
compensates for the absence of normal proteins or interacts with
some abnormal protein already in the cell to interrupt its
function. Gene therapy is not yet a routine treatment for any
disease, but it may become so as researchers solve the many
technical problems it presents.

Humans are prey to numerous diseases due to single-gene defects,

such as adenosine deaminase deficiency
(defective enzyme ), cystic fibrosis (defective ion channel), and
Duchenne muscular dystrophy (defective muscle protein).
Replacement of the defective gene is conceptually simple, but
practically very difficult. Effective gene therapy requires delivering
the gene to each cell in which it acts, integrating the gene with the
thousands of others on the chromosomes and regulating the
expression of the gene.
Gene delivery is a major hurdle. Viruses are the most commonly
used vehicle, or vector , since they have been designed by
evolution to deliver their own genes to our cells. Adenovirus (a type
of cold virus) has been the most commonly used vector, since it can
carry a very large gene and will infect most cell types. However, the
immune system is designed to prevent this type of infection, and
immune rejection has so far thwarted most gene therapy efforts.
While most patients have not been harmed by this problem,
one gene therapy patient has died from immune response to the
adenovirus. Modifications of the virus, using fewer immunogenic
viruses (such as adeno-associated virus, herpes virus, or
retrovirus), immune-suppressive drugs, and nonviral delivery
systems are all possible solutions. Curiously, the brain does not
mount a strong immune response, and as such, represents a
promising site for gene delivery in neurological diseases.

Getting the gene to enough target cells is also a significant

challenge. Adenosine deaminase deficiency affects white blood
cells and causes severe combined immune deficiency ("bubble boy"
disease). This disease can be treated by removing white blood
cells, inserting the adenosine deaminase gene into them, and
returning the cells to the bone marrow. Cystic fibrosis presents a
much bigger challenge, since it affects the airways and pancreas.
Inhalation of the vector may treat the lungs, but the pancreas is
more difficult to reach without injecting vector into the bloodstream.
Duchenne muscular dystrophy is an even bigger challenge, since it
affects all muscles, and muscles make up 45 percent of the body.
The only realistic treatment option in this case is systemic delivery,
which poses the added challenge of preventing delivery to
nonmuscle tissue.

Once inside the target tissue, genes usually become active whether
or not they are integrated into the host chromosome. However,
long-term expression requires that the gene join the host
chromosome. Directing the gene to do so, and to integrate in a way
that doesn't disrupt other genes, is still a significant challenge.
Regulating its expression, so that enough of the protein (but not too
much) is made, is also a problem. Currently, most virally delivered
genes do not integrate successfully, and stop making protein after
several weeks to months.

While correction of gene defects was the original inspiration

for gene therapy research, treatment of other diseases is now being
explored. Cancers are an appealing target, and several strategies
are possible. Currently the most promising is delivering a so-called
"suicide gene," whose protein product renders a tumor more
sensitive to cell-killing drugs, allowing lower doses of chemotherapy
to be effective. This works well for solid tumors, which can be
injected with the gene. Delivery to more diffuse locations is still
problematic. Further research on cellular properties of cancer cells
may broaden the reach of this and similar cancer-targeting
strategies.

See also Chromosome, Eukaryotic; Crick, Francis; Gene; Genetic

Diseases; Mendel, Gregor; Recombinant DNA

Richard Robinson

Bibliography
Lemoine, N. R. Understanding Gene Therapy. Oxford: BIOS
Scientific Publishers, 1999.

Lewis, Ricki. Human Genetics: Concepts and Applications, 4th

ed. New York: McGraw-Hill, 2001.

Stolberg, Sheryl Gay. "The Biotech Death of Jesse Gelsinger." New

York Times Magazine (28 November 1999): 17.
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Gene Therapy
The Columbia Encyclopedia, 6th ed.

Copyright The Columbia University Press

Gene therapy, the use of genes and the techniques of genetic

engineering in the treatment of a genetic disorder or chronic
disease. There are many techniques of gene therapy, all of them
still in experimental stages. The two basic methods are called in
vivo and ex vivo gene therapy. The in vivo method inserts
genetically altered genes directly into the patient; the ex vivo
method removes tissue from the patient, extracts the cells in
question, and genetically alters them before returning them to the
patient.

The challenge of gene therapy lies in development of a means to

deliver the genetic material into the nuclei of the appropriate cells,
so that it will be reproduced in the normal course of cell division and
have a lasting effect. One technique involves removing cells from a
patient, fortifying them with healthy copies of the defective gene,
and reinjecting them into the patient. Another involves inserting a
gene into an inactivated or nonvirulent virus and using the virus's
infective capabilities to carry the desired gene into the patient's
cells. A liposome, a tiny fat-encased pouch that can traverse cell
membranes, is also sometimes used to transport a gene into a body
cell. Another approach employing liposomes, called chimeraplasty,
involves the insertion of manufactured nucleic acid molecules
(chimeraplasts) instead of entire genes to correct disease-causing
gene mutations. Once inserted, the gene may produce an essential
chemical that the patient's body cannot, remove or render harmless
a substance or gene causing disease, or expose certain cells,
especially cancerous cells, to attack by conventional drugs.

Gene therapy was first used in humans in 1990 to treat a child with
adenosine deaminase deficiency, a rare hereditary immune disorder
(see immunity). Gene therapy has since been used experimentally
to treat a number of conditions, including advanced metastatic
melanoma, a myeloid disorder, and a rare hereditary condition that
leads to severely impaired vision. Despite the hope that gene
therapy can be used to treat cancer, genetic diseases, and AIDS,
there are concerns that the immune system may attack cells treated
by gene therapy, that the viral vectors could mutate and become
virulent, or that altered genes might be passed to succeeding
generations. In a few instances trials have been halted when a
patient has died or developed disease after undergoing gene
therapy.

In the United States, gene therapy techniques must be approved by

the federal government. The Recombinant DNA Advisory
Committee of the National Institutes of Health oversees gene
therapyexperiments. Like drugs, products must pass the
requirements of the Food and Drug Administration. Gene therapy is
a competitive and potentially lucrative field, and patents have been
awarded for certain techniques.

See J. Lyon and P. Gorner, Altered Fates: Gene Therapy and the
Retooling of Human Life (1995).
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Gene Therapy
A Dictionary of Biology
© A Dictionary of Biology 2004, originally published by Oxford University Press 2004.

Gene therapy The application of genetic engineering techniques to

alter or replace defective genes. A defective gene may result from
an incorrect sequence of bases in the DNA molecule or an inability
of the gene to code for the expression of a particular polypeptide.
Techniques currently being investigated involve the transfer of
normal genes into the genetic material of the cell to replace the
defective gene and the use of antisense RNA to ‘knock out’
defective genes in certain tissues. Retroviruses are often used
as vectors for transferring genes into cells as part of the natural
retrovirus life cycle involves the insertion of their own genetic
material into the chromosomes of their host.
Alternatively liposomes may be used. Gene therapy is being
developed in an attempt to cure and prevent such genetic diseases
as cystic fibrosis.
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Gene Therapy
A Dictionary of Nursing
© A Dictionary of Nursing 2008, originally published by Oxford University Press 2008.

Gene therapy n. treatment directed to curing genetic disease by

introducing normal genes into patients to overcome the effects of
defective genes, using techniques of genetic engineering. At
present, gene therapy is most feasible for treating disorders caused
by a defect in a single recessive gene, such as adenosine
deaminase (ADA) deficiency, severe combined immune deficiency,
and cystic fibrosis. Gene therapy for certain types of cancer is also
undergoing clinical trials.
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Gene Therapy
The Oxford Pocket Dictionary of Current English
© The Oxford Pocket Dictionary of Current English 2009, originally published by Oxford
University Press 2009.

Gene ther·a·py• n. the transplantation of normal genes into cells in

place of missing or defective ones in order to correct genetic
disorders.
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