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 cramps. 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 years. 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 symptoms. "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 said. 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 factors. 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. 21205-1911.
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