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Gene therapy

Gene therapy is the introduction of genes in to a person's DNA in order to
treat disease.

Gene therapy is an emerging medical technology that involves the addition of
DNA to the human genome in order to replace a defective gene or to provide a
gene the body can use to fight disease. Although the technology is still in
its infancy, it has been used successfully to treat genetic disorders such
as those encountered by children with immune deficiencies.

Background

In the 1980s, advances in genetics had already enabled human genes to be
sequenced and cloned. Scientists looking for a method of easily producing
proteins, such as the protein deficient in diabetics - insulin, investigated
introducing human genes to bacterial DNA. The modified bacteria then produce
the corresponding protein, which can be harvested and injected in people who
can not produce it naturally.

Scientists took the logical step of trying to introduce genes straight in to
human DNA, focusing on diseases caused by single-gene defects such as
Hemophilia, muscular dystrophy and sickle cell anemia. However, this has
been much harder than modifying simple bacteria, primarily because of the
problems in carrying large sections of DNA and delivering it to the right
site on the genome.

Types

It is possible to alter the DNA of somatic (normal body) cells or germline
(sperm or egg) cells. In somatic gene therapy, genes are delivered in to
body cells where they would be used to produce proteins. In highly
controversial germline engineering, DNA contained in sperm or egg cells are
changed so that the patient, and any offspring that he or she may produce,
will grow up with a modified genome. This type of gene therapy is not being
actively investigated in humans due to the ethics of changing DNA that would
be inherited by countless generations in the future.

Somatic gene therapy can be broadly split in to two categories: ex vivo
(where cells are modified outside the body and then transplanted back in
again) and in vivo (where genes are changed in cells still in the body.)

Ex vivo

The ex vivo approach was the first to be put in to practice. In 1990 trials
were run designed to treat children with an inherited immune defficiency, as
well as children or adults with high serum cholestorel levels. Cells were
removed from the patients body and incubated with vectors to introduce the
genes. Vectors are simply any mechanism that allows genes to be carried in
to the genome. Many vectors are based on viruses. After modification, the
cells are transplanted back in to the patient where they would hopefully
replace the defective gene in the original genome. The new gene would
correct the protein deficiency.

This technique is best used for diseases where the desired cells can be
extracted easily, such as the blood or liver.

In vivo

For in vivo techniques the challenge of inserting the genes is even greater.
The vector carriers have a difficult task to complete: they must deliver the
genes to enough cells for results to be achieved; they have to remain
undetected by the body's immune system; and they must deliver the genes in
to the precise spot on the genome for the body to recognize it and produce
the corresponding protein.

Much hope has been placed in viruses to carry the DNA. After all this is
what viruses do naturally - change cell's DNA in order to allow themselves
to reproduce. Through millions of years of evolution viruses have developed
very sophisticated ways of doing this. There are two classes of virus which
look promising - retroviruses and adenoviruses.

Retroviruses are small RNA based viruses. They reproduce by integrating
their RNA in to the host's DNA. Scientists have modified these viruses'
genetic code so that non of their natural proteins are produced, meaning
they can not replicate and damage the host. Because retroviruses target only
fast growing cells there are being investigated with an aim to developing
cancer treatments. RPR Gencell (a french pharmaceutical company) conducted
experiments injecting retroviruses in to lung cancer patients. After the
injections of vectors containing p53 - a gene that suppresses tumours -
directly in to the cancerous tissue, the tumours stopped growing and were
broken down by the body.

Adenoviruses are larger DNA based viruses. These can hold more genes and are
not limited to just targetting fast-dividing cells. However because the
larger size inevitably makes them more difficult to manipulate.

A problem affecting all virus-based vectors is recognition by the immune
system. When familiar viruses are detected in the bloodstream the body sends
antibodies to bind to and consume them. A second problem is the
unpredictablity of where the virus inserts the gene in to the DNA. If the
gene is inserted in the wrong place - for example inbetween an important
gene, or within intron regions that are rarely read - then the cell could
start behaving irregularly and the engineered gene would not be expressed.

Scientists are researching an interesting way of bypassing the DNA problems
by actually introducing an extra chromosome in to the body. Existing
alongside existing DNA, this 47th chromosone would contain the genes needed.
Introduced in to the body as a large vector, it is not expected to be
targetted by the immune system because of its construction.

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