GLUTAMATE TRANSPORTER COULD BE KEY
TO BETTER ALS DRUGS

SAN DIEGO, Nov. 14, 2001 — MDA-funded scientists say that finding new drugs to clean up toxic levels of the brain chemical glutamate could be the key to treating amyotrophic lateral sclerosis (ALS) — a fatal disease that currently has no effective treatment.

ALS attacks muscle-controlling nerve cells (motor neurons) in the brain and spinal cord, in most cases leading to paralysis and death within three to five years of diagnosis.

In a study on mice, the scientists showed that a genetic boost of "glutamate transporter" protein offered more protection against the disease than any drug treatment that's been tested so far. In mice, it extended life several times as long as does riluzole, the only currently approved drug for ALS.

The researchers announced those results Tuesday at the Society for Neuroscience annual meeting in San Diego.

Glutamate normally acts as a chemical messenger between neurons, but at high levels, it can be toxic. Cells called astrocytes use the glutamate transporter — known as EAAT2 — to vacuum up excess glutamate and protect neurons. But for reasons that aren't clear, many people with ALS have reduced levels of the EAAT2 protein, and the resulting accumulation of glutamate appears to damage motor neurons.

Rilutek (riluzole) works by blocking glutamate release. But it extends life by just a few months in people with the disease and by just two weeks in mice with the disease.

Jeffrey Rothstein of Johns Hopkins University in Baltimore and Margaret Sutherland of George Washington University in Washington hope to come up with more potent drugs that work by activating EAAT2.

To test that idea, Rothstein and Sutherland introduced extra copies of the EAAT2 gene into mice that normally develop ALS. (The mice have a mutant version of the SOD1 gene, linked to familial ALS.)

"With the glutamate transporter, we can increase mouse survival not by two weeks, but by a minimum of two months and a maximum of one and a half years," Rothstein announced.

Rothstein and Sutherland also used a fluorescent tag to visualize the EAAT2 protein, and found that astrocytes change their EAAT2 production in response to cues from motor neurons. That setup should allow the team to quickly screen for drugs that increase EAAT2 production, Sutherland said.