The discovery of penicillin in 1928 is one of medical science’s most remarkable stories: a laboratory “accident”—mold growing on a petri dish—led to the wonder drug of the 20th century and to a class of medicines that have saved millions of lives worldwide. Almost eight decades later, a modern-day derivative of penicillin, ceftriaxone, is being harnessed for a completely new and unanticipated use: a possible treatment for amyotrophic lateral sclerosis (ALS), the fatal neurodegenerative disease that afflicted Lou Gehrig.
This time, the finding was no accident. It came as a result of a systematic, federally funded analysis of 1,040 Food and Drug Administration approved medications. The unprecedented effort, which began in 2002 and involves 26 research laboratories nationwide, was designed to uncover just such novel uses for drugs already proved safe. Ceftriaxone is the first prominent success of the drug-screening initiative, having been identified by several different laboratories for actions against specific molecular targets believed to be involved in ALS and other neurodegenerative diseases.
“That was exactly the hope, that we would find these unknown mechanisms that no one else would be focused on.”
Follow-up experiments in a mouse model of ALS showed that the drug slowed the loss of motor neurons and muscle strength, and modestly lengthened survival. A clinical trial in people with ALS is slated to begin in July, with funding provided by the National Institute of Neurological Disorders and Stroke (NINDS).
In the drug-development world, that time frame—just three years from the earliest positive laboratory results to human testing—is “blazingly fast” compared with the usual seven to ten years, says Don Cleveland, an expert in neurodegeneration at the University of California at San Diego, who wrote a commentary on the results in the January 21 Science magazine.
No one knows if ceftriaxone, which belongs to a family of antibiotics known as beta lactams, will truly prove to be an effective treatment for ALS; many drugs that show promise in preclinical studies fail in human trials. But the finding has been met with enthusiasm within the ALS patient community and among scientists, even self-proclaimed skeptics of the screening approach such as Cleveland, who initially questioned the worthiness of searching for new mechanisms of action in existing drugs.
“The enthusiasm comes from the fact that this effort has enabled a scientifically well-documented compound to come to clinical trial in an amazingly short time, coupled with the scientific discovery of a completely unexpected use for a tried-and-true, proven-safe drug,” Cleveland says.
Such progress is especially important for diseases such as ALS, for which there are no effective treatments, Cleveland says. Moreover, in ALS as in other relatively uncommon diseases such as Huntington’s disease or spinocerebellar ataxia, pharmaceutical companies have been largely unwilling to invest the millions of dollars necessary to develop drugs marketable only to comparably small groups of patients.
“The concept that drugs have many mechanisms that they work on is not surprising, but the outcome of beta lactams was extremely unexpected,” says Lucie Bruijn, science director for the ALS Association, one of the non profit organizations that partnered with the NINDS to underwrite the screening effort. “And that was exactly the hope, that we would find these unknown mechanisms that no one else would be focused on.”
In the case of ceftriaxone and its cousins in the beta lactam family, the “unknown mechanism” that was discovered is its ability to increase brain levels of a protein known as a glutamate transporter, which essentially acts as a vacuum cleaner to suck up excess glutamate from the spaces between nerve cells. Glutamate is the most prominent “excitatory” neurotransmitter in the brain, activating neighboring nerve cells to relay nerve signals. Too much glutamate is known to be toxic to nerve cells and has been linked to a wide range of neurological disorders, among them ALS, stroke, Huntington’s disease, epilepsy, multiple sclerosis, and brain tumors. Glutamate also plays important roles in normal memory and learning processes, making it an attractive target for pharmaceutical development.
“Big [pharmaceutical companies have] long been interested in glutamate transporters as a target, but to date no one has found a drug that works at that level,” says Jeffrey Roth-stein, a John Hopkins neuroscientist who has spearheaded the investigations with ceftriaxone. Most medications act to block a receptor on a cell surface to interrupt a particular cellular action, he says, “but we needed a drug that would make the transporter work more efficiently, so it’s a hard target.”
Rothstein’s team used preserved slices of spinal cord that contained both neurons and astrocytes, the brain support cells that produce the glutamate transporter, to develop an assay that would detect which drugs could increase the levels of the transporter. They bathed the slices in the medications, one by one, not knowing which drugs they were testing, and then waited to see if any generated the action they were hoping for. When the compounds were unblinded, they realized that the drugs that were producing much more protein all belonged to the beta lactam class of antibiotics.
If it proves to be effective in people with ALS, the ceftriaxone story may be the first real help so many patients are waiting for. In any case, the tale of the discovery of its previously unknown action is destined to join the annals of medical history, born as it was from a unique public-private partnership that essentially sought to “squeeze blood out of rock—to squeeze as much out of existing drugs and do better for patients with neurological disease,” as Rothstein says.