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, 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:

 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 diagram depicting this process.

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 a retrovirus.
 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 19.

 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. 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 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?

 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. Read BBC article.
 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 Release.

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 Blindnessat
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. See Gene 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. See Gene Therapy is First Deafness 'Cure' at
NewScientist.com (February 11, 2005).

 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).

 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).

 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).

 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 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?