Searching for the Mouse
that Roars
Why more is better when it comes to ALS mimics.

When the first ALS gene surfaced in 1993, patients’ pulses weren’t the only ones to quicken. Scientists, too, felt a rush, especially since, for once, it looked like the lab techniques that could push the discovery into a cure were ready.

Philip Wong’s new dynactin model mimics ALS like no other.

The ability to engineer transgenic mice—those carrying human genes—had come into its own. What could better help overcome the illness than to endow mice with the mutant SOD1 gene, then track what goes wrong? The models would also prove the best testing ground for the drugs sure to follow.

It probably didn’t matter that the mouse model was based on a single mutant gene in just 1 percent of ALS patients; the bulk of the downhill path must hold for anyone with the disease.

Two years later, the drug riluzole was the first developed with the SOD1 mouse models. The animals lived longer. And when trials went to patients, they, too, seemed helped: The therapeutic track was set. Just fine-tune the drug target. Test the mice and higher animals and move into human trials. Next stop: the cure.

But it hasn’t worked that way.

Involved in generating some of the first mutant SOD1 mice, Packard researchers have worked it inside out. They’ve varied the single gene’s mutations to get animals with telling variations in their disease. They’ve developed SOD1 rats that mimic aggressive ALS. They’ve crossed the models with mice carrying other gene defects or with key genes knocked out. Or new genes knocked in. Or extra copies of perhaps-protective genes. And what have these animals taught us? ALS is far more complex than it originally looked—broader than what riluzole aimed to fix.

With this news has come—like an anvil from the sky—the realization that we need more models of ALS. “As good a tool as SOD1 has been,” says Center Director Jeffrey Rothstein, “it doesn’t wear enough hats. It isn’t turning out to predict therapies for sporadic ALS, as we’d hoped.”

So Center scientists have pushed for “the mouse that roars”—a single model or a collection of models that, as a whole, will shout out what causes the disease and tell which therapies are likely to transfer to patients.

Here, then, is a sampling of models—some brand new—from Packard Center labs.

• Sindbis, an animal virus, attacks neurons. Adult rodents that survive have motor neuron death and paralyzed hind legs. Unlike ALS, Sindbis doesn’t touch upper motor neurons—those from the brain to the spinal cord. But its effect may be identical on the lower motor neurons from spinal cord to muscle. Recently, Douglas Kerr showed that, as in ALS, spinal cords of virus-attacked mice and rats are unable to clear toxic glutamate away from motor neurons, for the same reasons.

Now used extensively by a Packard team to test stem cells’ ability to repair spinal cord damage, the Sindbis model is proving its worth.

• Studying mice with an ALS-like disease, Elizabeth Fisher found things amiss in axonal transport, the internal system that circulates nutrients and supports materials within neurons. Shortly after, advisor Kenneth Fischbeck came upon patients whose neurodegenerative disease also came from an error in axonal transport, though from a slightly different one. Family members had a mutation in the gene for dynactin, a protein cog in the transport system’s motor.

Now, Philip Wong has created a dynactin mouse—one that carries the flawed gene—and Wong’s fellow researchers say, with no little excitement, that it resembles ALS more than any model they’ve seen. Dynactin mice typically die at eight months after an ALS-like decline with paralysis. Motor neurons disappear. Like ALS patients, the models accumulate abnormal structural proteins. Their motor neurons become irritable early on, in an ALS-like way, and muscles atrophy similarly.

• Following injury from stroke, tumors, epilepsy or ALS, microglia, the nervous system’s chief immune cells, not only begin to divide but also secrete potentially toxic molecules. As part of his work on the role of microglia, Jean-Pierre Julien recently created a mouse model in which those cells’ rapid dividing is blocked. In his model, Julien can target dividing microglia at will and destroy them. The next step is seeing what effect that has in neurodegenerative disease.

• Zebrafish may be the ALS patient’s friend. Almost transparent, zebrafish have advantages over mouse and rat models, mostly because they develop so quickly. Add a human gene to a zebrafish egg, for example, and effects appear in organs barely three days later. Also, the huge number of offspring—one female has about 250 fry a week—raises studies’ reliability. Now Wim Robberecht is developing the first ALS zebrafish in hopes of finding genes that increase risk of sporadic disease. “We can also easily study axon repair in the fish,” he says, “because the motor neurons are so large.” Drug screening would also be far less expensive with the model.

Next > Vantage Point
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.