Finns Fight Free Radicals

Gene therapy tool would target free radicals
By Patrick BarryWeb edition : Friday,
September 26th, 2008
New method would make the most of the balance between the good and bad
of free radicals
Gene therapy has been touted as a possible way to cure genetic
diseases, but new research suggests that it could also fight the wear
and tear that leads to cardiovascular diseases.

An excess of free radicals can cause damage that often contributes to
heart disease and atherosclerosis (hardening of the arteries). But
some kinds of free radicals also benefit cells by serving as signaling
molecules that relay information as part of the cells’ normal
operation.

To work within this delicate balance, researchers in Finland have
developed a way to insert into human cells free radical–fighting genes
that only get switched on when free radical concentrations are high.
That way, the genes could stave off the worst effects of free radicals
without inhibiting the molecules’ useful functions, the researchers
report in the September Gene Therapy.

The technique “would be very useful in gene therapy because you have a
more focused expression of what you want. It’s not on when it’s not
needed,” comments Stefan Ryter of Brigham and Women’s Hospital and
Harvard Medical School in Boston. Ryter studies how the oxidative
damage done by free radicals alters proteins and other molecules in
cells, and how those changes are linked to disease . Seppo Ylä-
Herttuala and colleagues at the University of Kuopio in Finland
engineered a virus to carry an anti–free radical, or antioxidant, gene
called heme oxygenase-1, or HO-1. To control when the gene is active,
the researchers coupled it to a short piece of genetic code that
normally controls when a different antioxidant gene in cells switches
on and off. In experiments using human cells, the team showed that
this combination could produce the protein encoded by HO-1 in response
to oxidative stress caused by free radicals.

“We’ve been proposing HO-1 therapies for years,” Ryter says. “Not just
our group, but the whole field.”

In previous research on lab animals, adding a gene that fights the
oxidative effects of free radicals alleviated various cardiovascular
diseases. But in large studies on people testing whether antioxidants
such as vitamin E reduce the chance of heart disease, those taking the
antioxidants actually had a slightly higher risk for the disease.

While these results muddy the role of antioxidants for reducing
cardiovascular disease in humans, Steven Steinhubl of The Medicines
Company based in Parsippany, N.J., noted in a recent paper that the
right kind of antioxidant therapy might still have a beneficial
effect.

“It is critical to remember that the lack of benefits seen in clinical
trials to date does not disprove the central role of oxidative stress
in atherosclerosis,” Steinhubl wrote in the May 22 American Journal of
Cardiology. “Most antioxidant therapies that have been tested were not
chosen because they were proved to be the best antioxidants, but
rather because of their easy availability. An excellent example is
vitamin E. ... In some studies, vitamin E has been shown to have some
pro-oxidant effects.”

Steinhubl notes that in smaller studies using different antioxidants,
patients did see some benefit.

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