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Biotechnology and Society---Part
24
Gene Therapy Part 1
Learning is like rowing upstream; not to advance is to drop back.
--Chinese proverb
What is gene therapy?
A medical condition or illness
is like a malfunctioning piston in the engine of your automobile. One can ignore
it and hope it would rectify itself (most likely it will not). It can be
temporarily “fixed” by pouring some additives in the gas tank. However, the
long-term solution is to replace the malfunctioning piston (if it is available
for your car) if the engine and the automobile are to be kept in full function.
Many illnesses result from
genetic flaws (or mutations) in one’s genes. Such mutations cause the protein
encoded (if the protein is made at all) by the gene to malfunction. The illness
will not go away if you ignore it nor will there be a permanent restoration to
health if short-term measures (such as taking ineffective drugs) are adopted. If
the defective gene is replaced with a healthy functioning gene (assuming that is
possible) the illness can be cured. Welcome to the world of gene therapy!
In theory, gene therapy, which
means replacing a defective gene with a healthy one, is a simple solution to the
illness but is fraught with practical difficulties. Scientific advances in gene
therapy research are looking promising while the risks are equally glaring.
However, just because something is difficult one does not give up on the
venture. If successful, gene therapy can fix the problem at its source. While
progress is being made in overcoming the obstacles and difficulties, much
research and development need to be done before its full potential can be
realised. Gene therapy is a new frontier being explored in healthcare. Let us
examine the details and implications of gene therapy.
Targets for gene therapy:
It is currently estimated that
there are more than 4,000 distinct genetic diseases. The list of classic
diseases for which the responsible gene has been isolated and analysed is a
short one but growing fast. Choosing the right targets for gene therapy involves
answering some fundamental questions such as: (1) Is the medical condition a
result of mutation(s) in one or more genes? (2) Do we know which genes are
involved in the mutation(s)? (3) Do we have purified normal genes? (4) Do we
know the complete biology of the disorder? (5) Will the new gene incorporation
fix the problem? (6) Is it feasible to deliver the gene to the target without
much problem?
Once we have answers to the
questions raised above and the target(s) identified, then the delivery issue
must be addressed. The gene that we try to incorporate must target the right
cells. Once incorporated, the new gene must be 'turned on' for it to do its
work. It must also integrate in the target cell permanently and not slough off.
On top of all this, the side-effects must be mitigated. The Hippocratic
principle, “Do no harm” must prevail in any attempt to rectify the genetic
defect.
Tools for gene therapy:
Having the target(s) identified
and the supply of the normal gene are only the initial steps in gene therapy.
For delivery into diseased cells appropriate vehicles or 'vectors' are needed. A
vector can be any species which can carry the gene to the target, such as
viruses, synthetic concoctions such as liposomes (hollow entities in the shape
of tennis balls which can contain the gene inside and transport the gene
precisely to the target), or just plasmids (circular piece of DNA which has
genes in addition to the therapy gene). Whichever vector is used, it must be
customised to suit the specific needs of the particular disorder.
Using the virus is a very
efficient means to carry a gene into a cell. There are so many diseases caused
by viruses and they all do their job “well”. This requires precise delivery
to the target cells. If we choose a viral vector, the first step is to make sure
we denude the virus of any disease-causing potential and make sure that the
virus is suited to enter the target cells. The virus must then be modified so
that it can’t replicate (multiply) and destroy the target cell.
A virus can only be of limited
size and it cannot 'expand' to accommodate a large piece of adventitious genetic
material. Some tailoring or engineering is needed to cast off unwanted elements
in the virus in order to accommodate our candidate gene. In addition, a virus
can cause immune response in the body since it is an alien entity. If the immune
response is efficient, then the virus, along with the therapeutic gene, will be
eliminated. If that occurs then the purpose of using the virus to carry the gene
is defeated.
Some non-viral vectors such as
plasmids would also be good vehicles. Plasmids are circular pieces of DNA which
bacteria have engendered in order to exchange genetic material between
themselves as well as other cells. Plasmids can be isolated from bacteria and
tailored to incorporate the therapeutic gene.
Liposomes, which are lipid
molecules with specific groups to enclose the gene within their cavities, can
also be used to contain the therapeutic gene and deliver to the target. But each
vehicle has some specified and unspecified problems. The choice of a particular
vehicle has to be made on a trial-and-error basis in the laboratory.
Laboratory to clinic
Once the gene and the vector are assembled, additional work must be done before
taking it to the clinic for trials on patients or healthy volunteers. As
mentioned before, the biology of the disorder must be well documented. A proper
treatment protocol must be developed and approved by the committee appointed for
the purpose. A biological (preferably animal) model must be developed and the
effectiveness must be tested in the model. Finally, the safety of the procedure
must be established.
Challenges
There are several obstacles - both anticipated and unanticipated - which must be
overcome in the course of taking it to the clinic. The targeting must be very
specific. The gene must be delivered only to the diseased cell and not to other
healthy cells where they can do some harm. Also the gene must not cross into the
“germline” where the gene will be incorporated into the sperm or egg and
carry it to future generations. Even if the gene is delivered to the right
target, it may not function effectively, if at all. The gene must be activated
or 'turned on' through appropriate control/regulatory mechanisms.
Safety
The safety issue cannot be over emphasised. Side-effects from the treatment must
be minor. Finally, the incorporated gene must continue to work in the target
cell - i.e., it must become part of the cell’s genome and go through the
regular process of getting copied into all the divided cells.
The story of Jesse Gelsinger is
a case in point with respect to safety. Jesse Gelsinger was a 19-year-old with a
rare liver disorder who volunteered for gene therapy in 1999 at the University
of Pennsylvania. He participated in the well-conceived clinical trial that was
supposed to bring him back to health. He died of complications from an
inflammatory response shortly after receiving a dose of an experimental
adenovirus vector. His death dealt a blow to the confidence of scientists and
halted all gene therapy trials in the US for some time. The trials have
restarted after a countrywide conference was convened to discuss various safety
issues. Currently, several clinical trials are in progress for various genetic
disorders and the results are mixed.
Another safety issue concerns
the delivery to the right target cells. In the late 1990s a gene therapy trial
was undertaken to treat several children who suffered SCID (severe combined
immune deficiency syndrome) and were forced to live in a germ-free environment
thereby assuming the moniker, 'bubble boy'. The gene therapy trial was intended
to restore the function of a crucial gene, gamma C, to the cells of the immune
system. The trial was successful. However, two children developed leukemia as a
result of misincorporation of the gene in a second target. Those cells went out
of control causing leukemia. The children were treated with chemotherapy but the
situation raises a safety issue, nevertheless.
In the second part of this
article we will examine the current state of research and clinical trials for
some specific diseases.
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