It may spark a new approach to ALS therapy, researchers say.
A Packard Center research team has shown that a "cocktail" of three
prescription drugs significantly prolongs life and improves strength in
a standard mouse model of ALS, also known as Lou Gehrig's disease.

Most mice receiving the combination lived six weeks longer than their
non-drug littermates-a notable extension in animals that typically
survive under a year. The cocktail also delayed loss of muscle strength
and onset of other ALS-like symptoms in the mice by a month.

According to biochemist Jean-Pierre Julien, Ph.D., who led the
research team at McGill University in Montreal, "The three drugs
together show a clear neuroprotective effect. We have evidence from
earlier work that the combination is better than the single drugs would
be on their own. So some sort of synergistic effect may be taking place,
we believe."

The study was supported by a grant from The Robert Packard Center for
ALS Research at Johns Hopkins.

The three drugs, minocycline, riluzole and nimodipine are presently
available for a variety of conditions. Minocycline is a tetracycline
antibiotic that Julien says is frequently prescribed for infections.
(The study showed, however, that its effect in the model mice isn't
because of its usual bacteria-fighting capabilities.)

Nimodipine lowers blood pressure and is usually given to people with a
brain hemorrhage, to try to lessen brain damage. It's also common as a
drug for migraine headaches. Only riluzole is prescribed for ALS-in
fact, it's the only FDA-approved drug for the disease, though its effect
in humans and in mouse models is modest.

"We picked the three drugs because they each target a different cell
pathway that's abnormal in ALS," says Julien. Minocycline may do good
by lessening inflammation or by blocking a cell's built-in cascade of
self-destructing reactions. Nimodipine works to slow abnormal movement
of calcium in cells and riluzole likely damps down abnormal release of a
nerve transmitter, glutamate that can be toxic to cells.

The study followed mouse models with the same human gene that triggers
an inherited form of ALS in some patients. The SOD1 gene they carry
produces a mutant protein in the animals that somehow prompts motor
nerve cell death and symptoms of the disease.

The test animals received the three drugs, before any disease symptoms
would normally have appeared, by eating specially-prepared animal chow.
They were monitored for muscle weakness and changes in behavior. The
researchers also compared numbers of motor nerve cells in the spinal
cords of treated animals with those of untreated. They tested the
animals for appearance of molecules that signal cell death pathways have
been turned on. Finally, they checked for an increase in inflammatory
cells called microglia, typically seen in the disease.

All of the negative signs were lessened or delayed in the treated mice.

"We're quite excited by these results," says Julien, "and we believe
they could support the principle of multi-drug treatment for ALS. We
hope they encourage more study."

The team's work appears in the March issue of Annals of Neurology.

The Robert Packard Center for ALS Research at Johns Hopkins University,
which sponsored the study, is an organization that targets leading
investigators worldwide for collaborative work on ALS. Packard Center
scientists and clinicians work aggressively and rapidly to develop new
treatments and find a cure for amyotrophic lateral sclerosis (ALS).
Research conducted by the Center is meant to translate from the
laboratory bench to the clinic in record time. It is the only
organization and Institution with a proven track record of moving drugs
reliably and rapidly from pre-clinical experiments to human trials.

Kriz, J., Gowing, G., Julien, J.P. Efficient three-drug cocktail for
disease induced by mutant superoxide dismutase. Published Online: 14 Feb
2003. Annals of Neurology

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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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