Pharmaceutical companies are trying to develop drugs to combatfatal diseases by using the uptil now ignored part of DNWs structure
FivF. years ago, nobody had heard of
'antisense' technology. Now there are
biotechnology companies based on it,
and antisense drugs are in clinical trials.
To understand antisense technology,
consider the double helix structure of
DNA that has two inter-locking strands
that make up genes, Usually, only one of
them makes sense - that is, only one of
them holds meaningful genetic information. The other, the antisense strand
is just a molecular mirror image, carrying an inverted message that the cell
does not use. But it turns out that
this strand is a simple and a potentially
powerful tool.
Two Indian scientists in the us
are today at the focal points of research
to develop antisense compounds as
therapies for dengue fever, yellow
fever, cancer, AIDS and other diseases.
They are Ramaswamy Narayanan of
Floffinann-La Roche Inc in New Jersey,
us, and Sudhir Agrawal, vice president
Hybridon Inc, a biotech firm in
Massachusetts.
The uncertainty about what anti-
sense drugs are doing inside the body
has caused some experts in the field to
argue that clinical trials have begun far
too soon. "It is too early to take these
things to human beings when we don't
even know how they are working in a
test tube," contends Narayanan. To
Agrawal it does not matter how the drug
works, if they end up helping AIDS
patients. "Despite all the other properties, we feet that if we find an antisense effect then we have a new drug," says
Agrawal.
One reason antisense technology
looked like the answer to
drug designers' prayers
is that it seemed to be simple and straightforward.
During the first step of
AF protein synthesis, in which
genes are copied into RNA,
only one strand of the
double-helical DNA is SO
transcribed. For a gene to
be useful, the information
it carries has to be turned
into a protein. This is done
in two steps. First, a molecule - known as messen-
get RNA - is copied from
the sense strand of the DNA.
J This molecule is then
transported from the cell's
nucleus - where the genes
are kept - to the main
body of the cell, where the
cellular machinery translates the messenger RNA into protein.
Thanks to gene sequencing, making
an antisense molecule is relatively
simple. Once a desired gene has been
identified and the order of its basis is
known, the mirror image molecule can
be readily synthesised. And even if
antisense technology does not provide
the answer to infectious diseases, it
may still be good at fighting more stable
targets, like cancers and genetic diseases.
The specificity of antisense means
that knocking out the action Of, say a
turnour-promoting gene may be
straightforward and bring with it
few side-effects. That would still be a
considerable triumph.
For example in angioplasty, a treatment for expanding the narrowed
coronary arteries, a tiny balloon is
inserted through a slim 'catheter' tube
along the interior of an artery to crack
and plough through fatty blockages. But
in up to half of these procedures, the
blood vessel narrows within six months
at the very spot where it was cleared.
Often the narrowing is caused by an
uncontrolled growth spurt of the
smooth-muscle cells that support the
artery's walls. Searching for a solution,
researchers have pioneered a gene
therapy that in rats has kept a cellular
messenger RNA from opening the floodgates to rapid duplication of smooth
muscle cells.
The therapy involves a compound
that is a member of the emerging class of
antisense agents that are believed to
block genetic messages. in trials on rats,
scientists at Massachusetts Institute of
Technology and Harvard Medical
School, both in the us, performed
balloon angioplasty on part of the neck
artery. They then coated the vessel's
outer layer with liquid infused with a
particular antisense agent that should
hilt a gene believed to trigger replication of smooLh-muscle cells. Tests done
two weeks later showed up to 90 per
cent of possible smooth-muscle cell
growth was prevented so that the artery
remained unblocked. Equally important, smooth-musclc cells supporting
the blood vessel were unharmed.
Whether these therapies are possible
- as well as safe and effective- in
people won't be known for at least the
next few years. So far, no one has actually
proven how these antisense agents work
and determined how extensive their
effects may be. For example an antisense
agent might tamper with more cellular
messages than the one targeted.
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