NEW DRUG THERAPIES
SHOW PROMISE IN MICE WITH ALS

ORLANDO, Fla., Nov. 7, 2002 – In experiments on mice, scientists have found several new leads in the search for effective drug treatments for amyotrophic lateral sclerosis (ALS), a fatal, adult-onset neurological disease.

ALS kills muscle-controlling nerve cells (motor neurons) in the spinal cord, leading to paralysis and death from respiratory failure, often within three to five years of diagnosis. About 10 percent of cases are genetic, but in most, the cause is unknown. The only FDA-approved drug treatment, riluzole (Rilutek), extends life by just a few months.

Riluzole works by limiting the ability of brain cells to release glutamate, a chemical that normally stimulates motor neurons, but accumulates to toxic levels in the spinal cords of people with ALS. Given evidence for other events in the disease process scientists are investigating the potential benefits of other drugs.

At the 32nd annual Society for Neuroscience meeting here Wednesday, two groups described their results after testing new drugs and drug combinations on mice that have a genetic form of ALS.

One group, led by M. Flint Beal at Cornell University in Ithaca, N.Y., showed that the mice — which carry mutations in a gene called SOD1 — live several days longer if they’re treated with iron-porphyrin. The compound is related to a chemical found in hemoglobin, an oxygen-binding protein in red blood cells, and is believed to counteract oxidative stress, a buildup of oxygen-based free radicals.

Iron-porphyrin extended survival of the SOD1 mice when given before or after disease onset, improved their motor performance and reduced the levels of malondialdehyde (an indicator of oxidative stress) in their spinal cords.

Beal’s group also tested the effects of inhibiting matrix metalloproteinases (MMPs), enzymes that activate proteins on the outer surfaces of cells. One type, MMP-9, is elevated in the spinal cords of SOD1 mice, possibly leading to the activation of tumor necrosis factor alpha (TNF-alpha), a cell surface protein that contributes to inflammation and cell death.

As a first pass at MMP-9 inhibition, Beal’s group deleted the MMP-9 gene in SOD1 mice; deleting both copies of the gene extended their survival by 31 percent.

Beal’s group has also treated the mice with an MMP inhibitor — developed by Roche Pharmaceuticals for treating arthritis and cancer — but the drug extended survival by just 10 percent.

Finally, a group led by Jean-Pierre Julien at McGill University in Montreal tested a triple-drug cocktail consisting of riluzole, minocycline and nimodidpine.

Minocycline, an antibiotic believed to inhibit apoptosis (cell suicide), extends survival in SOD1 mice by about three weeks and is being tested in ALS patients in an clinical trial funded by the Muscular Dystrophy Association. Nimodidpine is used to treat brain hemorrhage, and works by blocking the entry of calcium into neurons — thought by some ALS experts to be an early event in motor neuron death.

SOD1 mice given all three drugs when they were in the early stages of ALS lived about six weeks longer than untreated mice did. Since all three drugs have FDA approval for treating different diseases, the triple-drug cocktail could be fast-tracked into clinical trials.