A two-pronged strategy for spinal muscular atrophy

Few diseases are more devastating than spinal muscular atrophy (SMA), both in terms of the disease's progression and outcome, and who its victims are. Like Lou Gehrig's disease (amyotrophic lateral sclerosis - ALS), SMA causes muscle wasting and loss of motor control, leading to death. But unlike ALS, SMA is a childhood disease, and is, in fact, the leading genetic cause of mortality in infants and toddlers.

Until now it has generally been believed that the "chicken" of neuronal deterioration and death preceded the "egg" of muscle deterioration, that SMA was purely a spinal cord neuron disease. But new work by HSCI Executive Committee members Lee Rubin, PhD, and Amy Wagers, PhD, turns that disease model on its head.

As Rubin explains, he and Wagers set out to test the hypothesis that SMA was essentially a motor neuron disease. "We isolated stem cells that give rise to muscle and found that there is a separate defect from the motor neuron defect. In mouse cells, both in vitro and in vivo, the muscle stem cells have a separate defect from that in the motor neurons," Rubin said.

This new research shows that the muscle stem cells "stop proliferating and prematurely start trying to make muscle, but they fail somewhere in the process," Rubin said. "The muscles are smaller because they fail to mature completely." And as Wagers has previously found, aging muscle has a very similar defect to SMA. While it had long been known that children with SMA had small muscles, it had been believed that was attributable to the neuronal disease. But the new finding sent Rubin and Wagers in a new direction, and "in a separate study," Rubin said, "we carried out a screen to look for drug-like molecules that can correct the defect seen in both SMA muscle and aging muscle. That screen was very successful, and we're putting together a paper now to report on it."

What the researchers now know, is that the muscle defect in SMA occurs prior to the motor neuron defect: What was thought to be the "egg" may, in fact, be the "chicken." "This is the opposite of what the disease was thought to be — a motor neuron disease that causes muscle problems; it may be, at least in part, that it's a muscle disease that leads to motor neuron problems," Rubin said.

He continued, "So it becomes important for us to correct the muscle problem. In a separate study that Amy and I have done together, we've tried to find drug-like molecules that can make the muscle grow better. These are molecules that are designed to make the muscle stem cells proliferate without differentiating, so there'll be the correct number of them, and they can help create more muscle." The next step will be to see what effect those molecules have on in vitro and in vivo models of the disease.