Washington: There is no specific drug to treat spinal muscular atrophy (SMA), a family of motor neuron diseases that in its most severe form is the leading genetic cause of infant death in the United States and affects one in 6,000 people overall. But a new multispecies study involving a drug that treats amyotrophic lateral sclerosis (ALS) has pinpointed a mechanism of SMA that drug developers might be able to exploit for a new therapy.
The research, published in the Journal of Neuroscience, reports that the drug Riluzole advanced neural cell development in a mammalian model of SMA and restored neuromuscular function and mobility in a Caenorhabditis elegans worm model of the disease.
Riluzole has already been tested as a therapy in a very small study of severely affected SMA patients. It failed to help. Nevertheless, what makes the new research encouraging, says Dr Anne Hart, professor of neuroscience at Brown University and senior author on the paper, is that the study traces the beneficial action of Riluzole to specific ‘SK2’ potassium channels in worm neurons. Humans have these channels too, and if they can be more precisely targeted by a new drug, she says, that could make a more meaningful difference, at least for some patients.
“We’re not suggesting based on this that SMA patients should ask their doctors for Riluzole,” Dr Hart says, “but we are suggesting that this pathway would be useful for therapeutic development.”
Because SMA has a lot in common with ALS, Dr Hart thought Riluzole might still be worth studying in the context of SMA. To do so, she partnered with fellow researchers at Boston Children’s Hospital. They worked in mouse neuronal cells while her team at Brown worked in the worms.
For each system, the researchers created SMA models in different ways by disabling the gene that produces the survival motor neuron (SMN) protein. Depletion of that protein causes SMA in people too.
In the mammalian neuronal cells, the Children’s Hospital researchers found that Riluzole promoted the growth of axons that was lacking in the SMN-depleted cells. However, Riluzole did this not by increasing SMN levels. Instead, the researchers found evidence that drug treatment matured the neurons more quickly in normal cells.
Most attempts to treat SMA have relied on trying to maintain or restore higher levels of SMN, Dr Hart notes. But Riluzole, or a future drug, may instead be able to work by accelerating cell maturity.
In the worms meanwhile, the Brown researchers found that Riluzole restored two important neuromuscular behaviours of SMA worms: the pumping action that allows the worms to move food through their digestive tracts and the body bending that they perform when swimming.
To learn how Riluzole had this effect, they performed further experiments testing various potassium channels, including SK2, that Riluzole is known to act upon. Losing these channels didn’t cause more problems in animals with less SMN protein, but losing the SK2 potassium channels in particular made neuromuscular function worse. Without the SK2 channels, the drug Riluzole didn’t improve function.
“This told us that Riluzole improves motorneuron function by acting through SK2 channels, which we did not know before,” says lead author Maria Dimitriadi, a postdoctoral researcher in Dr Hart’s group. “This is important because understanding how SK2 channels affect motorneuron disease may eventually lead to a treatment helping both ALS and SMA patients.”