| May 15, 2002
Can We Enlist Substitute Genes to
Fight Muscular Dystrophy?
Researchers Describe the Mechanisms Behind Dystrophy
PA) - Substitutes. If your teacher is out sick or the
secretary is on vacation, calling in a substitute is
always an option. But what if one of your genes is not
working? In recent years, researchers have eyed utrophin
as a substitute for a similar gene, dystrophin, which
is responsible for Duchenne's muscular dystrophy (DMD),
a fatal neuromuscular disease. In the May 15th issue
of the Journal of Neurological Sciences, researchers
at the University of Pennsylvania School of Medicine
detail the cellular mechanisms that promote and regulate
the transcription of the utrophin gene into protein.
Their findings may open the door to creating therapeutics
that will produce excess utrophin in people suffering
"Utrophin has been a major focus in muscular dystrophy.
Dystrophin and utrophin perform similar tasks at the
neuromuscular junction - where nerve cells meet muscle
tissue - and studies have shown that utrophin over-production
reverses the symptoms of muscular dystrophy in mice,"
said Tejvir S. Khurana, MD, PhD, assistant professor
in the Department of Physiology and researcher at the
Pennsylvania Muscle Institute at Penn. "It is not
a perfect substitute in the way that a putter is not
the same as a driver if you are playing golf, for example.
But when you are on the fairway and your driver is broken,
you can use your putter - you just have to hit the ball
much, much harder."
Duchenne's muscular dystrophy is one of the most frequent
hereditary diseases of men, affecting one in 3,500 boys.
DMD occurs when the dystrophin gene, located on the
short arm of the X-chromosome, is broken. Since males
only carry one copy of the X-chromosome, they only have
one copy of the dystrophin gene. Without the dystrophin
protein, muscle tissue cannot compensate sufficiently
and will eventually break down.
"Over-production of utrophin may be a viable alternative
to adding a working copy of the dystrophin gene through
gene therapy," said Khurana. "The available
research supports the idea that if you can crank up
the production of utrophin, you will compensate for
the lack of dystrophin."
In the article, Khurana and his colleagues describe
how specific intercellular signals, such as heregulin,
set into motion a series of reactions within the cell
that lead to the activation of the utrophin gene. In
cultured muscle cells, the researchers demonstrated
how heregulin ultimately switches on Sp1, a transcription
factor, which then binds to a specific region of the
DNA that drives the utrophin gene. Once attached to
DNA, Sp1, along with another heregulin-stimulated transcription
factor called GABP a/b, attracts the cellular machinery
responsible for transcribing genes into proteins.
The utrophin protein bears many functional similarities
to dystrophin, although it is expressed in more types
of cell tissue. At the neuromuscular junction, the two
proteins work as part of the complex network of molecules
that sustain muscle tissue through wear and tear. In
healthy muscle tissue, dystrophin works as a sort of
shock absorber to keep the cell membrane from tearing
apart during muscle contraction. Since it is so similar
to dystrophin, utrophin can also function as this molecular
shock absorber, although not as well.
The idea that utrophin has a protective effect against
DMD has been gaining favor as researchers looked deeper
into the causes of the disease. In fact, studies have
shown that disease progresses slowly in the first two
weeks after birth in dystrophin deficient mice, since
the levels of utrophin are still quite high, but much
more quickly in mice that lack both the utrophin and
"These findings will help define targets for stimulating
the muscle cells' native mechanisms into producing more
utrophin," said Khurana. "And while a substitute
isn't always as good as the original, in this case good
enough may well result in a substantial improvement."
Contributors to this study include Mads Gyrd-Hansen
and Thomas O.B. Krag of the University of Copenhagen,
Denmark and Alan G. Rosmarin of Brown University.
This work was supported by grants from the Dutch Duchenne
Parents Project (The Netherlands), the Muscular Dystrophy
Association (USA), Association Francaise contre Les
Myopathies (France), Statens Sundhedsvidenskabelige
Forskingsråd, the Lundbeck, Novo Nordisk, AP Møller
and Kong Christian den X Foundations (Denmark).
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is an international leader in biomedical research, medical
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as a major player on the world stage of medicine in
the 21st century.