MDA SCIENTISTS REPORT FIRST ‘HITS’
IN SCREEN FOR ALS DRUGS

ORLANDO, Fla., Nov. 6, 2002 — In part of an ongoing screen for new treatments of neurological diseases, researchers have found several candidate drugs that might be effective against amyotrophic lateral sclerosis (ALS), a fatal disease that can strike adults in the prime of life.

ALS kills muscle-controlling nerve cells in the spinal cord known as motor neurons, typically leading to paralysis and death within three to five years of diagnosis.

At the 32nd annual Society for Neuroscience meeting here, Jeffrey Rothstein and colleagues at Johns Hopkins University in Baltimore yesterday reported finding more than 20 chemicals with potential activity against glutamate – a brain chemical thought to contribute to ALS.

In previous research, Rothstein, who co-directs the Muscular Dystrophy Association's MDA/ALS Center at Hopkins, has linked ALS to increases in glutamate, which stimulates neurons, but becomes toxic with prolonged exposure. Normally, proteins called glutamate transporters vacuum up excess glutamate in the brain, but for reasons that aren’t clear, people with ALS have a deficiency of a transporter known as EAAT2 – apparently leaving motor neurons vulnerable to glutamate’s toxic effects.

Riluzole (Rilutek), the only FDA-approved drug for treating ALS, works by inhibiting the release of glutamate by brain cells. But it extends life by just a few weeks in mice with the disease and by a few months in people.

With an eye toward more powerful treatments, Rothstein has been searching for drugs that can boost EAAT2 levels.

The strategy has a good chance of success. At last year’s SFN meeting, Rothstein reported that when mice with ALS are genetically engineered to produce more EAAT2, their life span is extended by approximately 45 percent.

The drug screen is part of a larger effort coordinated by the National Institutes of Neurological Diseases and Stroke (NINDS) to find treatments for some of the most devastating neurological diseases, including Huntington’s disease, Parkinson’s, spinal muscular atrophy and spinal bulbar muscular atrophy. Rothstein’s lab is one of nearly 30 across the country — collectively known as the Neurodegeneration Drug Screening Consortium (NDSC) — using a variety of methods to test the effects of more than 1,000 chemicals, most of which are FDA-approved drugs.

The screen has started to bear fruit, but researchers are keeping tight-lipped about the results while they prepare the work for scientific publication.

Without giving away any details, Rothstein and his group presented results of their screen for EAAT2-enhancing drugs at today’s meeting. The group found 22 chemicals that stimulate at least a threefold increase in EAAT2 levels when tested on segments of rat spinal cord grown in laboratory dishes. They say many of these “hits” belong to a family of chemicals, set apart by a common structure and mechanism of action, but they won’t say which family.

There was also encouraging news regarding the NDSC’s results overall. Across the consortium, seven chemicals were hits in two or more of the ALS-specific tests, indicating that they might work against key parts of the disease process.

Next, Rothstein and his group plan to determine whether their 22 hits increase EAAT2 activity (not just abundance), and to test them in mice with ALS.