Vantage Point

What causes sporadic ALS? The longer we’re in the lab, the more it looks like a collection of defects, as though several mutant genes disrupt things just enough that, together, they overwhelm the body’s defenses and tip a person into disease. So we see simultaneous problems with clearing glutamate, having toxic free radicals, with riled immune cells, with cell transport—a rogue’s assembly.

That’s important to know if you want to develop an effective ALS drug. Say you have 10 patients with 10 different defects. If I tested drugs on an animal model that had only nine of the flaws, I’d miss the boat if I happened on a therapy against the 10th. I’d think my drug was worthless against ALS when it could really matter to people with defect 10.

So after a decade with riluzole, the single approved drug that neither stops nor reverses the disease, we in the ALS research community are doing serious soul-searching. That community, including the Packard Center, has tested more than 100 drugs, mostly in the classic mutant SOD1 mouse model. And though many performed far better in SOD1 mice than riluzole, they don’t help patients.

Has the SOD1 model wasted our time? Hardly. It continues to tell us how ALS behaves and, through understanding its biology, to expose meaningful targets for therapy. Yet it’s time for change. We’re developing better cell culture models, for one thing. Check our next ALS Alert to see stem cells’ potential there. And in this issue, you’ll read why Phil Wong’s dynactin mouse, for example, has us excited.

Finally, in case getting enough of a drug to the nervous system is the problem (see Wanted: A Therapy That Knows No Barrier), we aim to change that, too.

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