Johns Hopkins Gazette: September 18, 1995

Several Research Teams Battling ALS

Michael Purdy
Homewood News and Information 

     Lou Gehrig's doctors could tell him very little about the
mysterious disease that halted his legendary baseball career
after his 2,030th consecutive game, and they could do nothing to
slow or stop it.

     Nearly sixty years later, Baltimore Oriole Cal Ripken has
surpassed Gehrig's most admired baseball record, and the battle
against the disease that stopped Gehrig, amyotrophic lateral
sclerosis or ALS, continues.

     But researchers have cause to be hopeful.  They have new
leads on the possible causes of ALS; the first moderately
successful drug treatment for ALS is about to go to the Food and
Drug Administration for approval; and, thanks to the generosity
of Ripken, the Orioles, and a number of Baltimore businessmen,
leading neuromuscular disease researchers at Johns Hopkins have a
new endowment fund that will help support their continued
research into the causes and cures of ALS and similar diseases.

     The Cal Ripken, Jr./Lou Gehrig ALS Fund for Neuromuscular
Research was originally created through the sale of 260 special
on-the-field seats at the Sept. 6 game, where Ripken broke
Gehrig's consecutive games played record. Money from the seats--
which sold for $5,000 each--was supplemented by a pledge from the
Orioles, and new donations are continuing to flow into the fund.  

     "This new fund will provide critical support to the efforts
of our team and other Hopkins research teams who are trying to
bring the benefits of basic research to patients with ALS and
other neuromuscular disorders," said Ralph Kuncl, an associate
professor of neurology. 

     ALS currently afflicts approximately 30,000 people in the
United States.  Doctors estimate that about 1 out of every 800
men and 1 out of every 1,200 women alive today will eventually
develop the disease. First signs of ALS, which typically strike
between the ages of 35 and 65, include weakness in the legs or
arms, problems speaking or swallowing, and muscle twitching or

     The symptoms result from the death of motor nerve cells,
specialized nerve cells that control the movement of voluntary
muscles. Without chemical signals and essential nourishment from
motor neurons, these muscles weaken and atrophy, leading to
gradual paralysis and, in most cases, death within two to five

     In 1992 Kuncl, Jeffrey Rothstein, an associate professor of
neurology, and other Hopkins neuromuscular researchers linked
ALS-related motor nerve cell death to glutamate, an amino acid
that nerve cells use to send each other signals.  Glutamate
normally leaves a nerve cell and travels to a nearby nerve cell,
stimulating it at its surface and transmitting the message.

     Hopkins researchers showed that the cerebrospinal fluid of
ALS patients contained unusually high levels of glutamate, and
later linked these levels to a defect in a protein that
deactivates and recycles glutamate. They then proved that excess
glutamate can be toxic to motor nerve cells, effectively
stimulating them to death.

     "It's important not to characterize glutamate as 'the' cause
of ALS, though," Rothstein said. "It's more of a contributing
factor.  We still don't know enough about the defects in the
glutamate transporter protein to track down their cause yet, and
we and other researchers have shown that other factors can also
contribute to motor nerve cell death."

     Researchers were led to one such factor, an enzyme known as
superoxide dismutase 1, or SOD1, by familial ALS, a special type
of ALS that runs in families and makes up about 5 percent of
total ALS cases.

     SOD1 normally serves as a watchdog that seeks out and
disables free radicals, chemicals that can damage tissue.  Humans
have two copies of the gene for SOD1; in some cases of familial
ALS, one of these genes is defective. 

     "Scientists initially thought that this mutation simply left
sufferers with SOD1 levels that weren't sufficient to keep free
radicals from damaging and killing motor nerve cells," said David
Borchelt, an assistant professor of pathology who has studied the
effects of this mutation.

     Based in part on Borchelt's studies, Philip Wong and Michael
Lee, pathology instructors, created a genetically engineered line
of mice with a mutated SOD1 gene.  The mice developed ALS-like
     "Our mouse model and mouse models developed at other
institutions have shown that initial theories about SOD1 weren't
correct," Borchelt said. "Reduction or elimination of SOD1's
abilities to control free radicals isn't the crucial factor, at
least in mice.  Instead, the mutant SOD1 itself somehow becomes
toxic to mouse motor nerve cells."

     How do these different factors fit together?  Some theorists
believe that excessive glutamate and defective SOD1 may create a
fatal one-two punch that kills motor nerve cells.  Others see
glutamate and SOD1 as two of a number of delicate biochemical
systems thrown out of balance somehow in ALS.

      Even with the complete picture of ALS' complex causes still
unclear, new insights like these into potential causes of ALS are
helping researchers find and test potential new treatments.

     Hopkins findings about glutamate were crucial to the
selection of riluzole, the first moderately successful drug
treatment for ALS.  Recently submitted for approval to the FDA,
riluzole is believed to slow the production of glutamate, and has
been shown in clinical trials to moderately extend the lives of
ALS patients.

     "Riluzole's therapeutic effects are modest, but the drug is
a very important first step to more effective treatment," Kuncl

     Hopkins researchers have also played an important role in
the development of a new category of potential ALS treatments,
substances naturally produced by the body that are known as
neurotrophic factors. In the developing nervous system, these
factors help stimulate growth and guide budding nerve cells to
the right connections with other nerve cells; in the mature
nervous system, the factors are believed to help  nourish and
sustain nerve cells.

     "Our lab has shown that some of these factors have
remarkable abilities to prolong the lives of motor nerve cells
under adverse conditions," said Vassilis Koliatsos, an assistant
professor of neuropathology.  Koliatsos' research team has been
among the first to characterize how these factors naturally
assist neurons, and to demonstrate that in high doses three of
the factors can sustain motor neurons under stress.

     One of these factors, brain-derived neurotrophic factor, is
currently beginning secondary clinical trials at Hopkins, under
the supervision of neurologist David Cornblath, and at other
hospitals nationwide. Results from the initial trial are expected
to be presented soon.         

     The best may still be on its way.  Andrea Corse, a neurology
instructor, has recently used a culture of spinal cord cells to
show that the protective capabilities of glial-derived
neurotrophic factor are superior to all other known neurotrophic

     Trials of this factor's effects in animals are currently
under way, and plans are being made for trials in humans.

     Donations to the Cal Ripken, Jr./Lou Gehrig Fund can be
addressed to:

     Cal Ripken/Lou Gehrig Fund, c/o The Fund for Johns Hopkins
Medicine, Reed Hall, 1620 McElderry Street, Baltimore, Md. 

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