A Real Turn-On
Activating a gene—and a new principle—works so well in ALS models, it’s time for a trial.

A penicillin-related antibiotic sometimes used to treat meningitis may slow or help prevent nerve damage and death in ALS, according to a report by scientists mostly with the Packard Center and Johns Hopkins. Their work has led to a large, multicenter clinical trial to begin this spring.

Both lab-dish and whole-animal studies have made Center scientists optimistic.

In a report in the scientific journal Nature, the team describes studies with the drug ceftriaxone, using animals and lab cultures, that highlight its unusual ability to help cells mop up the chemical glutamate, well known as a source of nerve damage in ALS.

The overall result is both clear and strong. In mouse models of ALS, daily injections of ceftriaxone given just as symptoms first start delayed both nerve damage and the outward signs of the disease. Mice on ceftriaxone typically lived 10 days longer than those getting no drug—a significant advance in rodent terms.

The scientists are especially enthusiastic because ceftriaxone works on a principle that they’d thought only gene therapy could follow—and gene therapy’s usually a trickier way to correct flaws. The drug appears to turn on a gene that instructs nervous system cells to make glutamate transporters, molecules that pull excess glutamate out of the way before it does harm.

“We’re very excited by these abilities,” says Center Director Jeffrey Rothstein. “They show for the first time that drugs, not just genetic engineering, can increase numbers of specific transporters in brain cells.” Rats and mice that received daily ceftriaxone for up to a week had triple the usual amount of the transporter in cells, an effect that lasted some three months after treatment.

Normally, glutamate stimulates nerves so that electrical signals can travel from one to the next. But too much of the chemical overexcites nerve cells and harms them, as happens in ALS and some other diseases. Making more transporter molecules, however, seems to counter that. When added to cultures of nerve cells before they’re stressed—and stress typically triggers excess glutamate— ceftriaxone helps protect them. It also helps protect sections of spinal cord kept alive in culture and in tissue-culture models of stroke.

Because ceftriaxone helps only against glutamate damage—just one problem in ALS—it’s not surprising that the mice eventually succumbed to paralysis despite treatment, says Rothstein. “If we can find drugs that protect against other causes of nerve death in ALS, the combination might offer a real therapy, much like using drug combinations to treat cancer.”

Even though ceftriaxone is an antibiotic, its beneficial effect isn’t related to its ability to kill bacteria. “It would be extremely premature for patients to ask for the drug or to take it on their own,” Rothstein cautions. “Only a clinical trial can prove if it helps people and if it’s safe taken for a long time.”

Funding came from the Packard Center, the Muscular Dystrophy Association and the NIH. Project ALS provided the mice. Researchers from ALSA and Columbia University collaborated.

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