An experimental drug delays symptoms and prolongs survival in mice genetically engineered to have a condition similar to Lou Gehrig's disease -- a fatal, progressive paralysis also known as amyotrophic lateral sclerosis (ALS), researchers report.

The findings raise hope that the drug may also slow the disease in humans with ALS. Currently, there is no known cure for the disease, and most patients die within 5 years of diagnosis. However, much more study is needed before the experimental drug would be available to patients.

Inherited forms of ALS have been traced to mutations in the gene SOD1, and a family of proteins called caspases inside nerve cells plays a key role in the cellular suicide that marks the disease.

"Along with our similar work in Huntington's disease, these findings suggest caspases as a common thread in the (development) of several neurodegenerative diseases. Furthermore, the fact that a broad caspase inhibitor limits the progress of these conditions in animal models indicates its potential value in treating the human diseases," Dr. Robert Friedlander from Brigham and Women's Hospital in Boston, Massachusetts, told Reuters Health.

Friedlander, Mingwei Li, and their associates explored the role of caspases in mice with a form of ALS. Their findings are published in the April 14^th issue of the journal Science.

Two members of the caspase family, caspase-1 and caspase-3, were present and active in the spinal cords of mice with disease symptoms but not in mice that appeared normal, the authors report. Caspase-1 levels rose before those of caspase-3. Caspase-1 was also found at much higher levels in spinal cord cells from human patients with ALS, compared with cells from normal
individuals.

When the mice were given an experimental drug (zVAD-fmk) that blocks caspase activity, ALS-like symptoms were delayed by nearly 3 weeks, and survival was prolonged by almost a month, the results indicate.

The investigators confirm that the levels of active caspase-1 and caspase-3 were markedly reduced by treatment with zVAD-fmk. Furthermore, the stronger zVAD-fmk-treated mice had increased numbers of nerve cells in their spinal cords, compared with untreated mice.

These results "provide therapeutic information relevant to the human disease (and)... indicate that caspases play a role not only in the end stage of ALS but also in the (early) progression of the disease, which suggests that therapy targeted at inhibiting caspase function should begin (before
symptoms of ALS appear)," the authors conclude.

"zVAD-fmk probably extends survival after the onset of clinical disease by about 70%," suggest Mark Gurney from Genomics in Kalamazoo, Michigan, and colleagues in a related commentary. The body of evidence provides "a compelling argument for... the value of caspase inhibitors as potential therapeutic agents in the treatment of ALS and other neurodegenerative
diseases," the editorialists add.

SOURCE: Science 2000;288:335-339, 283-284.