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What is gene therapy?
Genes, which are carried on chromosomes, are the basic physical and functional
units of heredity. Genes are specific sequences of bases that encode instructions
on how to make proteins. Although genes get a lot of attention, its the
proteins that perform most life functions and even make up the majority of cellular
structures. When genes are altered so that the encoded proteins are unable to
carry out their normal functions, genetic disorders can result.
Gene therapy is a technique for correcting defective genes responsible for
disease development. Researchers may use one of several approaches for correcting
- A normal gene may be inserted into a nonspecific location within the genome
to replace a nonfunctional gene. This approach is most common.
- An abnormal gene could be swapped for a normal gene through homologous recombination.
- The abnormal gene could be repaired through selective reverse mutation,
which returns the gene to its normal function.
- The regulation (the degree to which a gene is turned on or off) of a particular
gene could be altered.
How does gene therapy work?
In most gene therapy studies, a "normal" gene is inserted into the
genome to replace an "abnormal," disease-causing gene. A carrier molecule
called a vector must be used to deliver the therapeutic gene to the patient's
target cells. Currently, the most common vector is a virus that has been genetically
altered to carry normal human DNA. Viruses have evolved a way of encapsulating
and delivering their genes to human cells in a pathogenic manner. Scientists
have tried to take advantage of this capability and manipulate the virus genome
to remove disease-causing genes and insert therapeutic genes.
Target cells such as the patient's liver or lung cells are infected with the
viral vector. The vector then unloads its genetic material containing the therapeutic
human gene into the target cell. The generation of a functional protein product
from the therapeutic gene restores the target cell to a normal state. See a
Some of the different types of viruses used as gene therapy vectors:
- Retroviruses - A class of viruses that can create double-stranded
DNA copies of their RNA genomes. These copies of its genome can be integrated
into the chromosomes of host cells. Human immunodeficiency virus (HIV) is
- Adenoviruses - A class of viruses with double-stranded DNA genomes
that cause respiratory, intestinal, and eye infections in humans. The virus
that causes the common cold is an adenovirus.
- Adeno-associated viruses - A class of small, single-stranded DNA
viruses that can insert their genetic material at a specific site on chromosome
- Herpes simplex viruses - A class of double-stranded DNA viruses that
infect a particular cell type, neurons. Herpes simplex virus type 1 is a common
human pathogen that causes cold sores.
Besides virus-mediated gene-delivery systems, there are several nonviral options
for gene delivery. The simplest method is the direct introduction of therapeutic
DNA into target cells. This approach is limited in its application because it
can be used only with certain tissues and requires large amounts of DNA.
Another nonviral approach involves the creation of an artificial lipid sphere
with an aqueous core. This liposome, which carries the therapeutic DNA, is capable
of passing the DNA through the target cell's membrane.
Therapeutic DNA also can get inside target cells by chemically linking the
DNA to a molecule that will bind to special cell receptors. Once bound to these
receptors, the therapeutic DNA constructs are engulfed by the cell membrane
and passed into the interior of the target cell. This delivery system tends
to be less effective than other options.
Researchers also are experimenting with introducing a 47th (artificial human)
chromosome into target cells. This chromosome would exist autonomously alongside
the standard 46 --not affecting their workings or causing any mutations. It
would be a large vector capable of carrying substantial amounts of genetic code,
and scientists anticipate that, because of its construction and autonomy, the
body's immune systems would not attack it. A problem with this potential method
is the difficulty in delivering such a large molecule to the nucleus of a target
What is the current status of gene therapy research?
The Food and Drug Administration (FDA) has not yet approved any human
gene therapy product for sale. Current gene therapy is experimental and
has not proven very successful in clinical trials. Little progress has
been made since the first gene therapy clinical trial began in 1990. In
1999, gene therapy suffered a major setback with the death of 18-year-old
Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine
transcarboxylase deficiency (OTCD). He died from multiple organ failures
4 days after starting the treatment. His death is believed to have been
triggered by a severe immune response to the adenovirus carrier.
Another major blow came in January 2003, when the FDA placed a temporary halt
on all gene therapy trials using retroviral vectors in blood stem cells. FDA
took this action after it learned that a second child treated in a French gene
therapy trial had developed a leukemia-like condition. Both this child and another
who had developed a similar condition in August 2002 had been successfully treated
by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID),
also known as "bubble baby syndrome."
FDA's Biological Response Modifiers Advisory Committee (BRMAC) met at the end
of February 2003 to discuss possible measures that could allow a number of
retroviral gene therapy trials for treatment of life-threatening diseases to
proceed with appropriate safeguards. In April of 2003 the FDA eased
the ban on gene therapy trials using retroviral vectors in blood stem cells.
What factors have kept gene therapy from becoming an effective
treatment for genetic disease?
- Short-lived nature of gene therapy - Before gene therapy can become
a permanent cure for any condition, the therapeutic DNA introduced into target
cells must remain functional and the cells containing the therapeutic DNA
must be long-lived and stable. Problems with integrating therapeutic DNA into
the genome and the rapidly dividing nature of many cells prevent gene therapy
from achieving any long-term benefits. Patients will have to undergo multiple
rounds of gene therapy.
- Immune response - Anytime a foreign object is introduced into human
tissues, the immune system is designed to attack the invader. The risk of
stimulating the immune system in a way that reduces gene therapy effectiveness
is always a potential risk. Furthermore, the immune system's enhanced response
to invaders it has seen before makes it difficult for gene therapy to be repeated
- Problems with viral vectors - Viruses, while the carrier of choice
in most gene therapy studies, present a variety of potential problems to the
patient --toxicity, immune and inflammatory responses, and gene control and
targeting issues. In addition, there is always the fear that the viral vector,
once inside the patient, may recover its ability to cause disease.
- Multigene disorders - Conditions or disorders that arise from mutations
in a single gene are the best candidates for gene therapy. Unfortunately,
some the most commonly occurring disorders, such as heart disease, high blood
pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the
combined effects of variations in many genes. Multigene or multifactorial
disorders such as these would be especially difficult to treat effectively
using gene therapy. For more information on different types of genetic disease,
What are some recent developments in gene therapy research?
Nanotechnology + gene therapy yields treatment to torpedo
cancer. March, 2009. The School of Pharmacy in London is testing a treatment in mice, which delivers genes wrapped in nanoparticles
to cancer cells to target and destroy hard-to-reach cancer cells.
Results of world's first gene therapy for inherited blindness
show sight improvement. 28 April 2008. UK researchers from the
UCL Institute of Ophthalmology and Moorfields Eye Hospital NIHR Biomedical
Research Centre have announced results from the world’s first clinical
trial to test a revolutionary gene therapy treatment for a type of
inherited blindness. The results, published today in the New England
Journal of Medicine, show that the experimental treatment is safe
and can improve sight. The findings are a landmark for gene therapy
technology and could have a significant impact on future treatments
for eye disease. Read Press
Previous information on this trial (May 1, 2007): A team of British
doctors from Moorfields Eye Hospital and University College in London
conduct first human gene therapy trials to treat Leber's congenital
amaurosis, a type of inherited childhood blindness caused by a single
abnormal gene. The procedure has already been successful at restoring
vision for dogs. This is the first trial to use gene therapy in an operation
to treat blindness in humans. See Doctors
Test Gene Therapy to Treat Blindness at www.reuters.com.
- A combination of two tumor suppressing genes delivered in lipid-based
nanoparticles drastically reduces the number and size of human lung
cancer tumors in mice during trials conducted by researchers from The
University of Texas M. D. Anderson Cancer Center and the University
of Texas Southwestern Medical Center. See Dual
Gene Therapy Suppresses Lung Cancer in Preclinical Test at www.newswise.com
(January 11, 2007).
- Researchers at the National Cancer Institute (NCI), part of the National
Institutes of Health, successfully reengineer immune cells, called lymphocytes,
to target and attack cancer cells in patients with advanced metastatic
melanoma. This is the first time that gene therapy is used to successfully
treat cancer in humans. See New
Method of Gene Therapy Alters Immune Cells for Treatment of Advanced
Melanoma at www.cancer.gov (August 30, 2006).
- Gene therapy is effectively used to treat two adult patients for
a disease affecting nonlymphocytic white blood cells called myeloid
cells. Myeloid disorders are common and include a variety of bone marrow
failure syndromes, such as acute myeloid leukemia. The study is the
first to show that gene therapy can cure diseases of the myeloid system.
Therapy Appears to Cure Myeloid Blood Diseases In Groundbreaking International
Study at www.cincinnatichildrens.org (March 31, 2006).
- Gene Therapy cures deafness in guinea pigs. Each animal had been
deafened by destruction of the hair cells in the cochlea that translate
sound vibrations into nerve signals. A gene, called Atoh1,
which stimulates the hair cells' growth, was delivered to the cochlea
by an adenovirus. The genes triggered re-growth of the hair cells and
many of the animals regained up to 80% of their original hearing thresholds.
This study, which many pave the way to human trials of the gene, is
the first to show that gene therapy can repair deafness in animals.
Therapy is First Deafness 'Cure' at NewScientist.com (February 11,
- University of California, Los Angeles, research team gets genes into
the brain using liposomes coated in a polymer call polyethylene glycol
(PEG). The transfer of genes into the brain is a significant achievement
because viral vectors are too big to get across the "blood-brain
barrier." This method has potential for treating Parkinson's disease.
Genes Slip into the Brain at NewScientist.com (March 20, 2003).
- RNA interference or gene silencing may be a new way to treat Huntington's.
Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs)
are used by cells to degrade RNA of a particular sequence. If a siRNA
is designed to match the RNA copied from a faulty gene, then the abnormal
protein product of that gene will not be produced. See Gene
Therapy May Switch off Huntington's at NewScientist.com (March 13,
- New gene therapy approach repairs errors in messenger RNA derived
from defective genes. Technique has potential to treat the blood disorder
thalassaemia, cystic fibrosis, and some cancers. See Subtle
Gene Therapy Tackles Blood Disorder at NewScientist.com (October
- Gene therapy for treating children with X-SCID (sever combined immunodeficiency)
or the "bubble boy" disease is stopped in France when the
treatment causes leukemia in one of the patients. See 'Miracle'
Gene Therapy Trial Halted at NewScientist.com (October 3, 2002).
- Researchers at Case Western Reserve University and Copernicus Therapeutics
are able to create tiny liposomes 25 nanometers across that can carry
therapeutic DNA through pores in the nuclear membrane. See DNA
Nanoballs Boost Gene Therapy at NewScientist.com (May 12, 2002).
- Sickle cell is successfully treated in mice. See Murine
Gene Therapy Corrects Symptoms of Sickle Cell Disease from March
18, 2002, issue of The Scientist.
What are some of the ethical considerations for using
--Some Questions to Consider...
- What is normal and what is a disability or disorder, and who decides?
- Are disabilities diseases? Do they need to be cured or prevented?
- Does searching for a cure demean the lives of individuals presently affected
- Is somatic gene therapy (which is done in the adult cells of persons known
to have the disease) more or less ethical than germline gene therapy (which
is done in egg and sperm cells and prevents the trait from being passed on
to further generations)? In cases of somatic gene therapy, the procedure may
have to be repeated in future generations.
- Preliminary attempts at gene therapy are exorbitantly expensive. Who will
have access to these therapies? Who will pay for their use?
Gene Therapy Links
Gene Therapy Clinical Trials
therapy studies in ClinicalTrials.gov - The U.S. National Institutes
of Health resource for public access to information on clinical research
- Gene Therapy
Clinical Trials - Access to a worldwide database of gene therapy
clinical trials at this Web site from the publishers of The Journal
of Gene Medicine. To search the database, click on "Interactive
Database" at the top of the page. Access to charts, statistics,
and abstracts from clinical trials results also provided.
Gene Therapy Journals
(Scientific, peer-reviewed publications targeted to clinicians and researchers.
Access to full-text articles in these journals typically requires a subscription.)
- Magazine of the Gene Therapy Center at the University of Alabama at Birmingham.
Issues available for download as PDF.