The rapid paralysis that killed baseball legend Lou Gehrig begins when neurons in the brain and spinal cord mysteriously die. Now, experiments with mice suggest a possible new treatment: drugs that fend off cell suicide.
Amyotropic lateral sclerosis (ALS), as Lou Gehrig's disease is officially known, cripples adults in their 40s and 50s and brings death within 1 to 5 years. The only available treatment just slightly increases chances of survival, but it works only in the early phase of disease. No other drugs were developed, because researchers simply had few clues about what was going wrong. A breakthrough came in 1993, when they discovered that a gene called SOD1 was mutated in many ALS patients. Just how the mutation leads to disease is still unclear, but studies of human patients and transgenic mice with the defective gene suggested that the mutation activates two enzymes called caspase-1 and -3. Caspases begin a process called programmed cell death, or apoptosis, which normally allows for the orderly disposal of aging, inefficient, or cancerous cells. Heightened caspase activity in ALS hinted that apoptosis runs amok, killing healthy and vital neurons.
To find out, neurosurgeon Robert Friedlander and colleagues at Brigham and Women's Hospital in Boston, Columbia University, and the University of Chicago first used several staining techniques to confirm that caspase was indeed activated in mice with the SOD1 mutation. Next, they used tiny pumps to infuse a trickle of a caspase inhibitor called zVAD-fmk directly into the brains of the mutated mice, while another group received infusions of a solution without the inhibitor.
The experiment was started when the mice were 60 days old; from then on, the animals receiving the caspase inhibitor took about 63 days to develop symptoms of ALS, 20 days longer than the control group. They also lived 27 days longer, the team reports in the 14 April Science. Microscopic examination of their spinal cords showed the treated mice had more motor neurons left than the controls. "We haven't found a cure," cautions Friedlander, but he's optimistic that the caspases may be a good lead for new drugs.
"The study offers an interesting new treatment approach," agrees pharmacologist Mark Gurney of Pharmacia Corp. in Kalamazoo, Michigan. "It's an important step forward," he adds--"but it's not a home run."