New Drug Screen: Uncle Sam’s Grand Present

Center Director Jeffrey Rothstein and researcher Sarjubhai Patel translated results of a key assay into hard numbers that could mean therapy for ALS patients.

Late this summer, 12 potential new ALS drugs—a jaw-dropping number—made their way into the Center’s first stages of animal testing thanks to an unusual project linking Center scientists and researchers across the country. What’s more, because the drugs are already in this country’s pharmacies for other non-ALS illnesses, if they test worthwhile in animal models and in ALS patient trials, they could arrive at clinics with unheard-of speed.

“They’re really a present,” says Center Director Jeffrey Rothstein about the agents, which came from a pool of 1,040 that the National Institute of Neurological Disorders and Stroke (NINDS) picked last winter for a quick-and-not-so-dirty screen of existing drugs. The pool contained a variety of FDA-approved agents: Antibiotics, anti-convulsants, anesthetics and arthritis medicines were among the mix. NINDS divvied the testing of the drugs—29 tests—among 26 laboratories focusing on ALS or other neurodegenerative diseases.

The labs were chosen because each has one or more well-tested assays that act like miner’s canaries for neurodegenerative disease. The Center’s assay for example—one of 10 especially relevant for ALS—focuses on measuring levels of EAAT2, a molecule that ferries the potentially toxic nerve transmitter glutamate out of harm’s way. In both humans with ALS and animal models, levels of EAAT2 drop greatly, “so any drug that raises levels is worth watching,” Rothstein says.

At the end of the six-month screening period, a dozen drugs stood out because they boosted EAAT2 levels from 300 percent to 700 percent. “Those are significant increases,” Rothstein explains. “We know of nothing else that can do that.” Also, he says, the drugs were top “hits” in more than one ALS-useful assay, giving added push to move them on to animal trials.

That next stage, studies in standard SOD1 mouse models of ALS, has just begun and should take from six months to a year. Promising drugs will move on to clinical trials at the Center.

The beauty of the approach is that it provides a system for choosing “high alert” drugs for possible clinic use that doesn’t rely on scientists’ educated guesses. Instead, the numerical results of the 29 assays tell all. “The exciting thing,” Rothstein says, “is that it’s a whole new, scientifically-sound track for drug discovery, testing many pathways at the same time.”

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