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Gene Therapy Frequently Asked Questions
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, it’s 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
faulty genes:
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A normal gene may be inserted
into a nonspecific location within the genome to replace a nonfunctional
gene. This approach is most common.
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An abnormal gene could be
swapped for a normal gene through homologous recombination.
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The abnormal gene could be
repaired through selective reverse mutation, which returns the gene to its
normal function.
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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.
Some
of the different types of viruses used as gene therapy vectors:
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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 a retrovirus.
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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.
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Adeno-associated viruses
- A class of small, single-stranded DNA viruses that can insert their
genetic material at a specific site on chromosome 19.
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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 cell.
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. FDA has yet to make a decision based on
the discussions and advice of the BRMAC meeting.
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 in patients.
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,
see Genetic
Disease Information.
What
are some recent developments in gene therapy research?
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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. See Undercover
genes slip into the brain at NewScientist.com (March 20, 2003).
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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,
2003).
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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 11, 2002).
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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).
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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).
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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 gene therapy?
--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 by disabilities?
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?
Source: Human Genome Project Information
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