Gainesville,
FL (11/18/99)- In a small animal study with huge implications, University
of Florida researchers report successfully preventing hypertension (high blood
pressure) in rats using germ line gene therapy. While gene therapy studies
are well underway in humans, these typically involve introducing genes to
replace missing proteins with no permanent change in the host DNA. Germ line
therapy, in contrast, introduces genes directly into the nuclear DNA of an
organism, allowing the changes to be passed to subsequent generations.
Researchers have known for some time that blood pressure is regulated by
a protein called angiotensin which in turn is regulated by a protein called
ACE (angiotensin-converting enzyme). ACE converts angiotensin to an active
state that elevates blood pressure and regulates blood flow in the kidneys.
Indeed, drugs that act on the enzyme, called ACE-inhibitors, have become a
mainstay of treatment. for high blood pressure.
"ACE inhibitors have revolutionized cardiovascular therapeutics in recent
years. However, their full impact in cardiovascular medicine has been limited
by their side effects, problems with patient compliance, and lack of mechanism
of action. Our objective in this study was to determine if targeting ACE activity
by genetic means would provide an improved therapy for hypertension,"
the researchers reported at a recent meeting of the American Heart Association.
The University of Florida researchers injected a genetic cocktail of ACE
antisense proteins on a adeno-associated virus vector directly into the heart
muscles of a species of hypertensive rats. The experimental proteins were
taken up by the heart muscle and integrated into the animals DNA. Both the
experimental animals and their offspring were protected from hypertension
and related organ damage to the kidneys.
"The neat part of this study is that we were able to show both the effects
on high blood pressure as well as on the organs involved in the control of
blood pressure. We have shown that this form of gene therapy not only prevents
these animals from developing high blood pressure but also prevents a lot
of other types of pathophysiological changes in the heart, the kidney and
the arteries," said Dr.Mohan K. Raizada, a molecular physiologist at the University
of Florida.
While it may be years before the approach is tested in people, the research
could represent a first step toward improving the treatment of, or even preventing,
high blood pressure and related health problems in humans, Raizada said.
"Our observations are very exciting in the sense that for the first time
there is a possibility of permanent control of high blood pressure involving
gene therapy," he said. "Where that leads to as far as human therapy is concerned
is far away. We have many hurdles to jump. For example, our studies have shown
we can prevent the development of high blood pressure. But in humans, there
are no gene markers to define that a person is going to develop high blood
pressure. The key would be to find therapies that would reverse high blood
pressure once it has been established."
Germ line gene therapy introduces permanent changes into the genome of a
organism and could produce unexpected negative consequences for subsequent
generations. This has been one of the main reasons this approach has not been
used in humans. It will take many years of animal studies before scientists
are ready to contemplate trying this approach in humans.
"We as scientists have got to be very careful. What are the physiological
consequences? We must not predispose ourselves to thinking there are no side
effect," emphasized Dr. Raizada
The research appears in the Nov. 12, 1999 issue of Circulation Research.
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