Cambridge International A Level Biology Revision Guide

Cambridge International A Level Biology
478
The most common vectors that are used to carry the
normal alleles into host cells are viruses (often retroviruses
or lentiviruses) or small spheres of phospholipid called
liposomes. Occasionally ‘naked’ DNA is used.
The first successful gene therapy was performed in
1990 on a four-year-old girl from Cleveland, Ohio. She
suffered from the rare genetic disorder known as severe
combined immunodeficiency (SCID). In this disorder, the
immune system is crippled and sufferers die in infancy
from common infections. Children showing the condition
are often isolated inside plastic ‘bubbles’ to protect them
from infections.
The defect in SCID involves the inability to make an
enzyme, adenosine deaminase (ADA) which is vital for
the functioning of the immune system. Some of the child’s
T-lymphocytes (page 230) were removed and normal
alleles of the ADA gene were introduced into them, using a
virus as a vector. The cells were then replaced. This was not
a permanent cure. Regular transfusions (every three to
five months) were necessary to keep the immune
system functioning.
Two years later, gene therapy using stem cells harvested
from bone marrow was successful, but in France, in 2000,
four children who had received gene therapy for X-linked
SCID developed leukaemia as a result of using a retrovirus
as vector. Retroviruses insert their genes into the host’s
genome, but they do so randomly. This means that they
may insert their genes within another gene or, more
dangerously, into the regulatory sequence of a gene, which
may then activate a nearby gene causing cancer.
Since then, researchers have used lentiviruses as
vectors. These also insert their genes randomly into the
host genome, but they can be modified to inactivate
replication. HIV has been disabled in this way to act as
a vector. The adeno-associated virus (AAV) is also now
used as a vector. This virus does not insert its genes into
the host genome and so they are not passed on to daughter
cells when a cell divides. This is a problem when the host
cells are short-lived (such as lymphocytes), but the virus
has been used successfully with long-lived cells such as
liver cells and neurones.
This work on vectors has led to increasingly successful
gene therapies in the last few years, including the following.
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The eyesight of young men with a form of hereditary
blindness, Leber congenital amaurosis, in which
retinal cells die off gradually from an early age, has
been improved.
The normal allele of the β-globin gene has been
successfully inserted into blood stem cells to correct
the disorder, β-thalassaemia.
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Six people with haemophilia B (in which factor IX is
missing) have at least seen their symptoms reduced.
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Five children were successfully treated for SCID in 2013.
We will look in more detail at the genetic disorder,
cystic fibrosis, to illustrate some of the problems facing
gene therapy.
Cystic fibrosis
Cystic fibrosis is a genetic disorder in which abnormally
thick mucus is produced in the lungs and other parts of
the body. A person with cystic fibrosis is very prone to
bacterial infections in the lungs because it is difficult for
the mucus to be removed, allowing bacteria to breed in
it. People with cystic fibrosis need daily therapy to help
them to cough up this mucus (Figure 19.18). The thick
mucus adversely affects many other parts of the body. The
pancreatic duct may become blocked, and people with
cystic fibrosis often take pancreatic enzymes by mouth
to help with digestion. Around 90% of men with cystic
fibrosis are sterile, because thick secretions block ducts in
the reproductive system.
Cystic fibrosis is caused by a recessive allele of the
gene that codes for a transporter protein called CFTR.
This protein sits in the cell surface membranes of cells in
the alveoli (and also elsewhere in the body) and allows
Figure 19.18 A person with cystic fibrosis is often treated with
‘percussion therapy’ – pummelling against the back to loosen
the thick mucus so that it can be coughed up.