ASSOCIATED PRESS

April 13 — Scientists have used a chemical to delay the onset of Lou Gehrig’s disease in mice and prolong their lives by blocking an enzyme crucial for cell death — a finding that holds promise not just for deadly Lou Gehrig’s disease but for other degenerative nerve disorders that afflict millions.

       THE HARVARD Medical School research may boost efforts already under way by half a dozen drug companies to create so-called “caspase inhibitors” safe enough to test in people suffering a variety of brain diseases.
       The new findings “provide a compelling argument ... for the value of caspase inhibitors,” Mark Gurney of the Pharmacia Corp., one drugmaker pursuing the compounds, wrote in a review accompanying the research in Friday’s edition of the journal Science.
       “The idea is very worthwhile, no question about it,” added Cornell University neurologist Dr. Flint Beal, although he cautioned that human testing is not yet planned.
       Some 30,000 Americans have Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis or ALS. No one knows the cause, but it results in a creeping paralysis as neurons, or nerve cells, in the brain and spinal cord that control movement are progressively destroyed. On average, patients die within five years of the first symptoms, as paralysis leaves them unable to eat or breathe.
       
ENZYME TIED TO OTHER BRAIN DISEASES
       Caspases are enzymes that signal a damaged or worn out cell to commit suicide. Scientists now believe that in a variety of brain diseases — from ALS and Alzheimer’s to Parkinson’s disease and strokes — caspases that should be lying dormant inside fairly healthy neurons are instead activated to kill them.
       If doctors could block the caspases’ action, they might be able to save important nerve cells.
       “That’s one of the things I find most exciting,” said Dr. Robert Friedlander of Harvard and Brigham and Women’s Hospital, who conducted the new ALS research. “A drug that’s going to work for one of these diseases is likely going to work” for several.
       Friedlander tested mice that were genetically engineered to get the human version of ALS. He implanted miniature pumps in their brains to bathe neurons with an experimental caspase-inhibiting chemical called zVAD-fmk

The treated mice showed ALS symptoms 20 days later than untreated mice — a long time in a mouse’s lifespan — and they lived 22 percent longer, he reports in Science.
       If humans had a similar result, that would equal another 14 months of life, said Dr. Leon Charash, medical adviser to the Muscular Dystrophy Association, which helped fund Friedlander’s work. In contrast, the only ALS drug sold today prolongs survival by about three months.
       Equally important, Friedlander stressed, was his discovery that caspases don’t just abruptly kill off a damaged cell. Instead, their activity in one cell is essentially contagious, affecting the secretion of toxic substances that make neighboring neurons too sick to work properly.
       
PROTECTS NEURONS
       So while “it’s not a cure,” he said giving zVAD to mice very early in the disease apparently protected some neurons that caspases had just started sickening.
       Would it work in people? Nobody knows, but Friedlander did find in the spinal cords of ALS patients some activated caspase identical to that in sick mice, a good sign.
       But pharmaceutical companies are waiting for a better drug before testing it in people, said Friedlander, who found similar results a year ago when he tested a caspase-inhibiting chemical in mice with Huntington’s disease, another incurable killer.
       He said he does want to test zVAD in people, but its maker fears it could cause serious side effects. The chemical was created solely for laboratory use, not as a potential human drug.
       The drug also would require direct infusion into the brain or spinal cord, “no trivial matter,” Cornell’s Beal cautioned. Still, he said, “This is a desperate illness” and he expects high patient demand for any caspase inhibitor that makes it to human testing.
       Half a dozen companies, including Pharmacia and drug giant Merck & Co., are trying to create caspase inhibitors. When asked if human tests were foreseeable within the year, Pharmacia’s Gurney said not with his company’s version; Merck officials didn’t comment.
       
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