The New Rat Model:
Bigger Is Better

Don Cleveland: his SOD1 rats will test new drug-delivery systems.

The right tools are crucial for the right job—whether it’s home repair or seeking a cure for ALS. Now, Center scientists with researchers from pharma company Wyeth-Ayerst have made a new rat model of the disease that’s far easier to work with and more versatile than earlier mouse models. That’s especially helpful with the dozens of stem cell studies coming from laboratories worldwide, work where cells must be injected with pinpoint accuracy into tiny neural targets.

“More important in understanding ALS,” says Center researcher Don Cleveland, Ph.D., “is that new studies with the rat model show some of the strongest evidence yet to link errors in the way cells handle the neurochemical messenger glutamate with the disease.”

In their approach, Center scientists inserted a mutant version of the human gene for superoxide dismutase (SOD1) into rats. SOD is an enzyme that helps cells prevent a buildup of toxic free-radical molecules. Mutations in the SOD1 gene are closely tied to inherited forms of amyotrophic lateral sclerosis. They account for nearly a fifth of familial ALS, though exactly how abnormal SOD sparks the disease is far from clear.

While scientists have used SOD1 mouse models for half a decade—they’re drug companies’ most common animal model of ALS—the mice are far from ideal “because, frankly, they’re just too small,” says Cleveland, “especially for delivering therapies with a surgical approach.”

Cleveland explains that a new reservoir system surgically implanted under the skin can release test drugs to the brain and spinal cord, bypassing natural barriers to large molecules. With the rats, scientists can use the reservoir system to test experimental approaches to therapy that would be impossible in smaller animals and too expensive in humans.

















Left: Model rat spinal cord before symptoms
Right: Similar spinal cord area 10 days later

The ALS-like disease the rats develop is similar to that in model mice. Both animals die in about 120 days. But there’s a key difference: the mouse’s downhill path is gradual. Rats, by contrast, first appear normal, then, 10 days before their demise, experience sudden, widespread death of motor neurons. “The onset and death follow each other really closely in rats,” says Center Director Jeffrey Rothstein, M.D., Ph.D. “This makes events surrounding the ‘death cascade’ in the spinal cord appear both dramatic and far more obvious than in mice.”

Before rat motor neurons died, researchers saw a clear drop in the ability of the spinal cord to “mop up” glutamate. A normal messenger between nerve cells, glutamate can trigger motor-cell death if released in large quantities. “The new rat offers real evidence that a consequence of the known SOD1 mutation is excess glutamate,” says Cleveland. “It gives us hope that therapies based on glutamate could be effective.”

Next > Vantage point
One of the most satisfying things about directing the Center has been watching the shift in our thinking about the biology of ALS.