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Duke Researchers Develop First Treatment for Rare Muscle Disease


Duke Health News 919-660-1306

DURHAM, N.C. – Researchers at Duke University Medical Center
have demonstrated for the first time that it is possible to
regenerate functional muscle in a rare type of muscular

Based on their successful tests in animals, they have been
working closely with the federal Food and Drug Administration
to begin using the treatment in children with a fatal
muscle-wasting condition called Pompe disease.

The injectable enzyme treatment was developed by Duke
pediatric medical geneticist Dr. Yuan-Tsong Chen. He said it is
the first therapy to show promise in any type of a genetic
muscle-wasting disease.

Muscular dystrophy is a broad category of inherited diseases
in which the body's muscles don't function normally. Usually,
an important muscle protein is missing or defective. Many
doctors have been unsure if it is even possible to regenerate
muscle tissue that has been damaged in these muscle-wasting
diseases. Chen has now shown it is possible in principle to
replace a missing component of muscle and improve muscle

"This is a major milestone is our long-term efforts to
develop an effective treatment for this devastating fatal
disease," Chen said.

The scientists reported their findings in the Feb. 15 issue
of the Journal of Clinical Investigation. The research was
supported by grants from Synpac Pharmaceuticals Ltd., the Japan
Health Science Foundation and the Muscular Dystrophy

Within this year, Chen and his colleagues expect to treat
children born with the rare and always fatal Pompe disease,
which is caused by an inherited defect that results in a
deficiency in an essential enzyme called acid alpha glucosidase

Normally the GAA enzyme helps the body break down stored
glycogen into glucose, a sugar the body uses for energy.
Without the active enzyme, stored glycogen builds up in the
body's muscles, eventually destroying them. About 100 children
are born with Pompe disease each year in the United States. In
a severe form, the disease is always fatal, usually within the
first two years of life.

Chen and Duke colleagues Helen Wen Yang, Mark Pennybacker,
and Johan L.K. Van Hove had been searching for an effective
treatment for Pompe disease for several years. The treatment
they developed is similar to that used to treat children with
the "bubble boy" disease, a deficiency in the enzyme adenine
deaminase (ADA). In each case, the first available treatment
was injecting a missing enzyme into the bloodstream.

"But for Pompe disease, previous attempts at enzyme
replacement therapy failed because the enzyme was not taken up
by the muscle cells," Chen said. "We circumvented this problem
by using the body's own system to get the enzyme inside muscle

Chen solved the problem by purifying a form of the enzyme
that has a modified residue attached to the sugar molecule of
the enzyme. The modified molecule is recognized by special
muscle cell receptors, which then trigger the cell to engulf
the enzyme and direct it to where it is needed.

The researchers used molecular biology techniques to insert
the human gene for GAA into a common type of cell grown in the
laboratory. These cells act like a mini-factory, churning out
human GAA enzyme. After several years of experimentation, Chen
and his colleagues obtained enough purified enzyme to begin
tests on laboratory animals.

Chen collaborated with Tateki Kikuchi and Nobutsune Ichihara
of the National Institute of Neuroscience, Tokyo, and Makoto
Mizutani of the Nippon Institute for Biological Science,
Kobuchizawa, Japan, who developed a strain of Japanese quail
also missing GAA. These birds can't fly and when turned on
their backs can't right themselves.

The team of researchers used three test groups of birds. Two
birds were injected with a high dose of purified human GAA, two
with a low dose of GAA, and two were injected with salt
solution. Each bird received seven injections over a 16-day
period. Two days after the last injections, the scientists
evaluated the birds' ability to right themselves.

The high-dose GAA treatment improved muscle strength so much
that both birds could right themselves when flipped on their
backs. One bird could even fly a short distance. Tests showed
these birds had an increase in GAA activity and decreased
muscle glycogen and improved muscle structure. The low-dose
birds showed similar improvements, but to a lesser degree.

Because quail GAA and its human counterpart are not
identical, researchers expected that the human form of the
enzyme would not be as effective in quail. Laboratory tests
revealed that quail muscle requires a higher dose of human GAA
to restore active enzyme levels to normal.

"Based on these results, we believe this enzyme is a
promising therapy for the human form of Pompe disease," Chen
said. He said he will initially attempt to treat only a small
number of children. "If it is successful, children will need a
supply of the enzyme for their whole lives," he said.

Synpac Inc. of Middlesex, England, will supply the enzyme
for the clinical trial.

Chen, one of a handful of experts in Pompe disease
worldwide, confirms diagnosis on children born with Pompe
disease in the United States.

He and his colleague Andy Amalfitano are also developing a
gene therapy strategy for treating Pompe disease. They hope to
inject a working copy of the gene into muscle cells using a
modified virus to carry the gene into cells. If successful, a
gene therapy strategy would allow the muscle to generate its
own enzyme and eliminate the need for lifetime injections of
the enzyme.

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