- What are genes?
Genes are the biological
units of heredity. Genes determine obvious traits, such as hair and eye color,
as well as more subtle characteristics, such as the ability of the blood
to carry oxygen. Complex characteristics, such as physical strength, may be
shaped by the interaction of a number of different genes along with environmental
influences.
Genes are located on chromosomes
inside cells and are made of deoxyribonucleic
acid (DNA), which is a type of biological molecule. Humans have between
30,000 and 40,000 genes. Genes carry the instructions that allow cells to
produce specific proteins,
such as enzymes.
To make proteins, a cell must first copy the information stored in genes
into another type of biological molecule called ribonucleic
acid (RNA). The cell's protein synthesizing machinery then decodes the
information in the RNA to manufacture specific proteins. Only certain genes
in a cell are active at any given moment. As cells mature, many genes become
permanently inactive. The pattern of active and inactive genes in a cell and
the resulting protein composition determine what kind of cell it is and what
it can and cannot do. Flaws in genes can result in disease.
- What is gene therapy?
Advances in understanding and manipulating genes have set the stage for scientists
to alter a person's genetic material to fight or prevent disease. Gene therapy
is an experimental treatment that involves introducing genetic material (DNA
or RNA) into a person's cells to fight disease. Gene therapy is being studied
in clinical trials (research studies with people) for many different types
of cancer
and for other diseases. It is not currently available outside a clinical trial.
- How is gene therapy being studied in the treatment
of cancer?
Researchers are studying several ways to treat cancer using gene therapy.
Some approaches target healthy cells to enhance their ability to fight cancer.
Other approaches target cancer cells, to destroy them or prevent their growth.
Some gene therapy techniques under study are described below.
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In one approach, researchers replace missing or altered genes with healthy
genes. Because some missing or altered genes (e.g., p53) may cause cancer,
substituting “working” copies of these genes may be used to
treat cancer.
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Researchers are also studying ways to improve a patient's immune
response to cancer. In this approach, gene therapy is used to stimulate
the body's natural ability to attack cancer cells. In one method under
investigation, researchers take a small blood sample from a patient and
insert genes that will cause each cell to produce a protein called a T-cell
receptor
(TCR). The genes are transferred into the patient's white blood cells
(called T lymphocytes)
and are then given back to the patient. In the body, the white blood cells
produce TCRs, which attach to the outer surface of the white blood cells.
The TCRs then recognize and attach to certain molecules found on the surface
of the tumor cells. Finally, the TCRs activate the white blood cells to
attack and kill the tumor cells.
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Scientists are investigating the insertion of genes into cancer cells
to make them more sensitive to chemotherapy,
radiation
therapy, or other treatments. In other studies, researchers remove
healthy blood-forming stem
cells from the body, insert a gene that makes these cells more resistant
to the side
effects of high doses
of anticancer drugs, and then inject
the cells back into the patient.
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In another approach, researchers introduce “suicide genes”
into a patient's cancer cells. A pro-drug (an inactive form of a toxic
drug) is then given to the patient. The pro-drug is activated in cancer
cells containing these “suicide genes, ” which leads to the
destruction of those cancer cells.
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Other research is focused on the use of gene therapy to prevent cancer
cells from developing new blood
vessels (angiogenesis).
- How are genes transferred into cells so that gene
therapy can take place?
In general, a gene cannot be directly inserted into a person's cell. It must
be delivered to the cell using a carrier, or “vector.” The vectors
most commonly used in gene therapy are viruses. Viruses have a unique ability
to recognize certain cells and insert genetic material into them.
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 grown outside the body. The gene is transferred
into the patient's cells while the cells are outside the patient's body.
In other studies, vectors (often viruses) or liposomes (fatty particles)
are used to deliver the desired gene to cells in the patient's body. This
form of gene therapy is called in
vivo, because the gene is transferred to cells inside the patient's
body.
- What types of viruses are used in gene therapy, and
how can they be used safely?
Many gene therapy clinical trials rely on retroviruses
to deliver the desired gene. Other viruses used as vectors include adenoviruses,
adeno-associated viruses, lentiviruses, poxviruses, and herpes
viruses. These viruses differ in how well they transfer genes to the cells
they recognize and are able to infect, and whether they alter the cell's DNA
permanently or temporarily. Thus, researchers may use different vectors, depending
on the specific characteristics and requirements of the study.
Scientists alter the viruses used in gene therapy to make them safe for humans
and to increase their ability to deliver specific genes to a patient's cells.
Depending on the type of virus and the goals of the research study, scientists
may inactivate certain genes in the viruses to prevent them from reproducing
or causing disease. Researchers may also alter the virus so that it better
recognizes and enters the target cell.
- What risks are associated with current gene therapy
trials?
Viruses can usually infect more than one type of cell. Thus, when viral
vectors are used to carry genes into the body, they might infect healthy
cells as well as cancer cells. Another danger is that the new gene might be
inserted in the wrong location in the DNA, possibly causing harmful mutations
to the DNA or even cancer.
In addition, when viruses or liposomes are used to deliver DNA to cells inside
the patient's body, there is a slight chance that this DNA could unintentionally
be introduced into the patient's reproductive
cells. If this happens, it could produce changes that may be passed on
if a patient has children after treatment.
Other concerns include the possibility that transferred genes could be “overexpressed,”
producing so much of the missing protein as to be harmful; that the viral
vector could cause inflammation
or an immune reaction; and that the virus could be transmitted from the patient
to other individuals or into the environment. Scientists use animal testing
and other precautions to identify and avoid these risks before any clinical
trials are conducted in humans.
- What major problems must scientists overcome before gene therapy becomes
a common technique for treating disease?
Scientists need to identify more efficient ways to deliver genes to the body.
To treat cancer and other diseases effectively with gene therapy, researchers
must develop vectors that can be injected into the patient and specifically
focus on the target cells located throughout the body. More work is also needed
to ensure that the vectors will successfully insert the desired genes into
each of these target cells.
Researchers also need to be able to deliver genes consistently to a precise
location in the patient's DNA, and ensure that transplanted genes are precisely
controlled by the body's normal physiologic signals.
Although scientists are working hard on these problems, it is impossible
to predict when they will have effective solutions.
- The first disease approved for treatment with gene therapy was adenosine
deaminase (ADA) deficiency. What is this disease and why was it selected?
ADA deficiency
is a rare genetic disease. The normal ADA gene produces an enzyme called adenosine
deaminase, which is essential to the body's immune
system. Patients with ADA deficiency do not have normal ADA genes and
do not produce functional ADA enzymes. ADA-deficient children are born with
severe immunodeficiency
and are prone to repeated serious infections,
which may be life-threatening. Although ADA deficiency can be treated with
a drug called PEG-ADA, the drug is extremely costly and must be taken for
life by injection into a vein.
ADA deficiency was selected for the first approved human gene therapy trial
for several reasons:
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The disease is caused by a defect in a single gene, which increases
the likelihood that gene therapy will succeed.
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The gene is regulated in a simple, “always-on” fashion,
unlike many genes whose regulation is complex.
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The amount of ADA present does not need to be precisely regulated. Even
small amounts of the enzyme are known to be beneficial, while larger amounts
are also tolerated well.
- How do gene therapy trials receive approval?
A proposed gene therapy trial, or protocol,
must be approved by at least two review boards at the scientists’ institution.
Gene therapy protocols must also be approved by the U.S. Food and Drug Administration
(FDA), which regulates all gene therapy products. In addition, trials that
are funded by the National
Institutes of Health (NIH) must be registered with the NIH Recombinant
DNA Advisory Committee (RAC). The NIH, which includes 27 Institutes and Centers,
is the Federal focal point for biomedical research in the United States.
- Why are there so many steps in this process?
Any studies involving humans must be reviewed with great care. Gene therapy
in particular is potentially a very powerful technique, is relatively new,
and could have profound implications. These factors make it necessary for
scientists to take special precautions with gene therapy.
- What are some of the social and ethical issues
surrounding human gene therapy?
In large measure, the issues are the same as those faced whenever a powerful
new technology is developed. Such technologies can accomplish great good,
but they can also result in great harm if applied unwisely.
Gene therapy is currently focused on correcting genetic flaws and curing
life-threatening disease, and regulations are in place for conducting these
types of studies. But in the future, when the techniques of gene therapy have
become simpler and more accessible, society will need to deal with more complex
questions.
One such question is related to the possibility of genetically altering human
eggs or sperm,
the reproductive cells that pass genes on to future generations. (Because
reproductive cells are also called germ
cells, this type of gene therapy is referred to as germ-line therapy.)
Another question is related to the potential for enhancing human capabilities—for
example, improving memory and intelligence—by genetic intervention.
Although both germ-line gene therapy and genetic enhancement have the potential
to produce benefits, possible problems with these procedures worry many scientists.
Germ-line gene therapy would forever change the genetic makeup of an individual's
descendants. Thus, the human gene pool would be permanently affected. Although
these changes would presumably be for the better, an error in technology or
judgment could have far-reaching consequences. The NIH does not approve germ-line
gene therapy in humans.
In the case of genetic enhancement, there is concern that such manipulation
could become a luxury available only to the rich and powerful. Some also fear
that widespread use of this technology could lead to new definitions of “normal”
that would exclude individuals who are, for example, of merely average intelligence.
And, justly or not, some people associate all genetic manipulation with past
abuses of the concept of “eugenics,” or the study of methods of
improving genetic qualities through selective breeding.
- What is being done to address these social and
ethical issues?
Scientists working on the Human Genome Project (HGP), which completed mapping
and sequencing all of the genes in humans, recognized that the information
gained from this work would have profound implications for individuals, families,
and society. The Ethical, Legal, and Social Implications (ELSI) Research Program
was established in 1990 as part of the HGP to address these issues. The ELSI
Research Program fosters basic and applied research on the ethical, legal,
and social implications of genetic and genomic research for individuals, families,
and communities. The ELSI Research Program sponsors and manages studies and
supports workshops, research consortia, and policy conferences on these topics.
More information about the HGP and the ELSI Research Program can be found
on the National Human Genome Research Institute (NHGRI) Web site at http://www.genome.gov
on the Internet.