To try for a quick advance in ALS therapy, a team of scientists has
branched out from the usual approach that centers on understanding the
cell biology of the disease. Instead, a group with the Packard Center
for ALS Research at Johns Hopkins is narrowly focusing on what's often
the immediate cause of death in ALS, the weakening of breathing muscles.
Their goal is to use gene therapy techniques to rescue dying nerves to
the diaphragm.

"If it works - and that's a considerable 'if, ' - such an approach
could significantly lengthen patients' survival with the disease and
improve their quality of life," says Jeffrey Rothstein, M.D., Ph.D., the
Center's director.

Recently, Packard Center scientists began several groundwork studies to
learn exactly how ALS affects breathing. The researchers also hope to
learn if the disease brings changes in body metabolism - something that
also would have an impact on a person's need for oxygen and, hence, on
breathing.

"As far as we know, nobody's ever charted the respiratory changes that
take place in a neurodegenerative disease such as ALS," says Center
physiologist Clarke Tankersley, Ph.D. The researchers are studying
animal models of ALS, mice with the same human gene that's disrupted in
the small number of people with the familial form of the disease.

"On a broad level," adds neurologist Jeremy Shefner, M.D., Ph.D., a
Center advisor with the SUNY Upstate Medical University at Syracuse,
"it's not clear in our mouse or rat models - or even, precisely, in
patients - what brings about their demise. It could be weakened
breathing, but malnutrition or even nutrition-related heart failure
could be at fault."

"But we'll need to know that, we'll need these basic studies to be able
to see if gene therapy makes a difference," says Tankersley. "Also,"
Shefner adds, "the studies will enable us to prove that a new therapy
targets what we think it's targeting." Both researchers say a better
understanding of respiration in ALS may also suggest other ways to ease
or extend patients' breathing ability.

In his studies, Tankersley follows several different strains of the
mouse models. He'll record breathing rate, for example, as well as the
amount of air the animals inhale and their metabolic rate. By examining
the model mice at 10, 14 and 17 weeks, he'll catch the period when their
breathing efficiency changes. In both ALS patients and model mice,
breathing strategies shift during the course of the disease. They move
from using the diaphragm to employing intercostals or rib cage muscles.
The latter technique, Tankersley says, uses more energy.

Shefner's focus is on the breathing muscles themselves. He measures the
diaphragm's ability to respond to nerve impulses, for example. He's
already noted characteristic differences in muscle behavior in the
course of the animal models' disease.

In parallel with the breathing studies, other scientists with the team
are working on the potential therapy end of things, readying approaches
specifically targeted to respiratory muscles and the motor neurons that
control them, sorting out ways to deliver therapy directly to the
phrenic nerve that stimulates the diaphragm and trying to anticipate
safety issues. "We hope that ultimately this will let us buy time for
patients," says Rothstein. "It's not a cure," Tankersley explains, "but
it's on the edge of preventing the problem that directly leads to
death."

Dr. Tankersley's laboratory is at the Bloomberg School of Public
Health, Johns Hopkins University.

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The Center for ALS Research at Johns Hopkins is a collaborative effort
by some of the best ALS and non-ALS scientists to aggressively and
rapidly develop new treatments and find a cure for ALS, also known as
Lou Gehrig's disease. It's the only institution of its kind dedicated
solely to the disease. Research conducted by the Center is meant to
translate from bench to bedside in an expedited time frame. Center
scientists from institutions around the world have made some of the most
important discoveries in ALS, leading to advances in understanding and
treatment of the disease.

The nature of ALS shapes the Center's aggressive, results-oriented
scientific approach. ALS is a devastating, progressive neuromuscular
disease that causes complete paralysis and loss of function -- including
the ability to eat, speak and breathe -- and eventually, death. ALS
progresses quickly and is not curable. Most patients die within five
years of diagnosis.

To learn more about The Center for ALS Research at Johns Hopkins,
including the latest information on ALS research and treatment, log on
to www.alscenter.org.
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