Picture a tiny baby in his crib. You’d expect him to be waving his arms and kicking his legs at the sight of his mother, but his limbs are flopped by his sides, and even turning his head to look at her is too much effort for him.
The leading genetic cause of death in infants and toddlers is a disease you may never have heard of: spinal muscular atrophy or SMA, a neuromuscular disease characterized by muscle weakness and atrophy.
In Type 1 SMA, the most severe form of the disease, babies show symptoms by six months of age, and rarely survive past their second birthday. Onset of milder forms of the disease is much later, even in adulthood. In all, up to 25,000 Americans have SMA, making it one of the least rare of rare diseases.
But now there’s hope for even the tiniest, most vulnerable SMA patients.
In December, following successful clinical trials, the U.S. Food and Drug Administration approved the first drug to treat children — even newborns — and adults with SMA: nusinersen, produced by the Biogen pharmaceutical company as Spinraza. The F.D.A. approval came after a successful clinical trial, demonstrating improved motor function in infants who were diagnosed with SMA before 6 months of age and who received their first injection of Spinraza when they were less than 7 months old. Remarkably, children who normally would have succumbed to their disease were not only alive but reaching major developmental milestones.
And before the drug trials in patients, research using mouse models provided the essential foundation of knowledge of the mechanisms of SMA.
Thirteen years ago, the SMA Foundation asked The Jackson Laboratory (JAX) to distribute mouse models of the disease to the biomedical research community. And over the past decade, work by JAX researchers in SMA has led to a new approach to modeling genetic diseases that could pave the way to many other breakthrough treatments.
“My lab started focusing on SMA research,” says Cat Lutz, Ph.D., director of the JAX Rare and Orphan Disease Center, “to find out what was needed to understand the disease in all its forms, from the lethal, early-onset Type 1 to the less severe Types 2 and 3, which are more common in the population because the patients survive longer.”
SMA is caused by defects in the SMN1 gene, which encodes the SMN protein. The SMN protein is critical to the health and survival of the nerve cells, known as motor neurons. Loss of motor neurons in the spinal cord and lower brain stem results in progressive muscular atrophy, in the most severe cases resulting in paralysis and loss of the ability to breathe or swallow.
SMA patients do not produce enough SMN protein, and the less SMA protein they produce, the more severe the disease. Moreover, disease severity also depends on the patient’s level of a second gene, SMN2, which somewhat compensates for faulty SMN1 function. As a result, SMA disease prognosis depends on how many copies of SMN2 are present. Two or fewer copies of SMN2 leads to earlier onset, more severe disease, while three or more copies provide enough function to result in a later-onset, milder form of SMA.
"It was clear that if we could restore levels of SMN protein in patients with SMA," Lutz said, "we could reduce the severity of the disease, but it was not clear exactly when SMN should be administered."
In 2011 Lutz, working with Umrao R. Monani, Ph.D., and colleagues at Columbia University, and researchers at Regeneron Pharmaceuticals Inc. and the SMA Foundation, reported in the Journal of Clinical Investigation on a new mouse model that opened up a new therapeutic path for the disease.
"Our special model of SMA allowed us to investigate the effects of turning on SMN expression at different time points during the course of the disease," Lutz explained at the time the paper was published. "We found that restoring the SMN protein even after disease symptoms appeared increased the survival of the mice and slowed down disease progression."
The researchers had also discovered that for the best effect, early administration of the SMN protein works best. "There was a therapeutic 'window of opportunity' during which the Type I, severe mice responded best to the SMN treatment," Lutz said. Mice treated later, after symptoms appeared, showed some improvement, but those treated after substantial neurodegeneration had already occurred failed to show therapeutic benefit. The Lutz lab went on to develop another model of SMA, in this case the mouse was representative of a type II patient. Encouragingly, the mice again showed benefit in response to treatment and again, the earlier the intervention the better the outcome
This work with a mouse model of SMA by Lutz and her colleagues lay the foundation for the successful clinical trials of Spinraza.
“A colleague once asked me why I was working so hard on a rare disease like SMA to benefit so few patients,” Lutz recounts. “The fact is, all the things we learn from these rare and orphan diseases will be applicable to Parkinson’s, Alzheimer’s and other diseases with bigger patient populations.
“And when you see kids with SMA actually walking and playing, who without treatment probably would not even be alive, that’s why we work so hard,” she says.