Vantage Point

Needle in a haystack. That’s what the hunt for ALS drugs has been like for too long. Though our approach has had direction—finding Riluzole, for example, was based broadly on stopping overstimulation of motor nerves—the search worldwide has leaned toward “let’s try this; let’s try that.”

And mouse models, even though they carry human genes for hereditary ALS, aren’t helping as much as we’d hoped. They’ve given us crucial insight into what the disease does. But they haven’t predicted treatment success well. Researchers have toted up more than 100 drugs that did fine in the ALS mouse but not in patient trials—Celebrex being the latest.

So it’s time to change our approach. With a push from new technology, we’re going to start rearranging the haystack so the needle becomes obvious.

Now our search for drugs will hinge largely on identifying paths that go wrong in all types of ALS. Basic science has told us that more than 40 genes and the pathways they’re on influence how motor neurons degenerate. We want to mimic those flawed pathways in lab dishes and look for agents to correct or compensate for them, so useful drugs will stand out. There’s no guarantee it’ll work, but it’s a rational approach.

We’ve used this tactic for the drug ceftriaxone (see A Real Turn-On): In all forms of ALS, reactions involving the glutamate nerve transmitter go astray, mitochondria fail and what’s called oxidative damage occurs. So when we screened 1,040 drugs, we tested for drugs that in some way alter these pathways. Ceftriaxone topped the list. We found its ability to boost a glutamate-removing molecule especially exciting. Now the Center hopes to build on this, to develop a host of different lab-dish assays to farm out nationwide. It could more than double our screening efforts.

Jeffrey D. Rothstein, M.D., Ph.D.
Director, The Robert Packard Center for ALS Research

Next > On Center
Constellation Energy Classic: Way Above Par