Pain reliever may help treat life-threatening childhood disease

A drug withdrawn from pharmacy shelves over 20 years ago may point the way to a new treatment for spinal muscular atrophy, or SMA, a muscle-wasting and often life-threatening childhood disease.

A new study suggests that the drug, called indoprofen, increases the production of a protein that is key to the survival of the nerve cells affected by the disease. Indoprofen was taken off the market in the early 1980s due to reports of serious gastrointestinal reactions as well as reports that the drug caused cancer in laboratory rats. Researchers are now looking into ways to modify the drug to make it less toxic to humans, said Arthur Burghes, a study co-author and a professor of molecular and cellular biochemistry at Ohio State University.

While SMA strikes only about one in 6,000 newborn Americans each year, it is the leading genetic cause of infant and toddler death in the United States as well as Western Europe. There is no cure or standard treatment, and children with the most severe form of the disease usually die before their second birthday. Motor neurons – nerve cells that send signals from the spinal cord to muscles throughout the body – rapidly deteriorate in SMA due to reduced levels of survival motor neuron (SMN) protein. Patients with the disease lack SMN1, a gene that produces SMN protein. For reasons that aren’t clear, this protein deficiency affects only motor neurons of the spinal cord – all other cells in the body function normally.

SMA patients do have one or more copies of SMN2, a gene that produces low levels of SMN protein. But these levels aren’t high enough to stop SMA’s deleterious effects on spinal motor neurons. Laboratory experiments using indoprofen to treat human fibroblast cells resulted in a 13 percent increase in SMN protein production in the cells. “This increase is sort of like giving an additional SMN2 gene to a patient – it would give the patient about 13 to 15 percent more protein,” Burghes said. “While this additional protection wouldn’t cure the disease, it could lessen the severity of symptoms.”

The study appears in the current issue of the journal Chemistry and Biology. Burghes worked with a team of scientists from Columbia University, the National Institutes of Health, the University of Massachusetts Medical School and a hospital in the United Kingdom. Brent Stockwell, the study’s principal investigator, is a researcher at Columbia University.

The researchers screened 47,000 chemical compounds to find ones that would boost SMN2’s protein production capabilities. Included in this group were a number of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. Out of all the compounds screened, indoprofen was the only drug – including the only NSAID – that showed an effect. Researchers used human fibroblasts taken from patients with Type I SMA, the most severe form of the disease. While SMA doesn’t harm fibroblasts, the cells still lack the SMN1 gene. “We can’t extract spinal neurons from humans, and the fibroblasts gave us a pretty good idea of indoprofen’s affect on human cells,” Burghes said.

SMN protein production increased by 13 percent in the treated fibroblasts.

“Theoretically, children with less severe forms of SMA may get even more protection than this, since these children have more copies of the SMN2 gene than do children with the most severe form,” Burghes said.

The researchers also tested indoprofen’s effects on mice pregnant with SMA offspring. “What is still unclear is at what point motor neurons most need the additional SMN protein,” Burghes said. “Should we give treatment once a patient has symptoms, before the symptoms start, or even in utero? We just don’t know.” Even so, indoprofen still gives researchers a good starting point for creating drugs to help treat SMA, he said. “The next step is to work on modifying the drug to make it an optimal compound for treating SMA, and to try to find other compounds that work in a similar way,” Burghes said. “Chemical modification of indoprofen will hopefully help us create a better drug.”

This work was funded by grants from Andrew’s Buddies, Families of SMA and the National Institutes of Health. Work in Burghes’ laboratory has also been supported by the Miracle for Madison fund at Ohio State.