An epilepsy drug that has been on the market for decades can ease the symptoms of adult sufferers with a genetic disorder that seriously weakens muscles, researchers at the School of Medicine have found.
The scientists retrospectively reviewed results from off-label use of the drug valproate to treat seven adult patients with spinal muscular atrophy (SMA). Clinicians offered the drug to patients based on research conducted elsewhere that showed that the drug increased levels of a key protein in cell cultures.
“The treatment has been fairly successful,” said lead author Chris Weihl, M.D., Ph.D., a postdoctoral fellow in neurology. “The drug appeared to be well-tolerated and increased the strength of the patients who took it.”
The study, now available online, appeared in the Aug. 8 issue of Neurology.
Weihl said that a larger, prospective trial is needed to firmly establish valproate as a treatment of choice for sufferers of this type of SMA.
Such trials are already under way elsewhere in pediatric patients who suffer from a different type of SMA that begins earlier in life. Weihl and his fellow researchers are concerned that valproate may not work as well in those patients. They wanted to make sure that researchers did not discard the possibility that valproate could help older sufferers even if the trials in pediatric patients went poorly.
“Based on what we know of the unique genetics of this disease, there was reason to think that this drug could be more helpful to patients who develop SMA later in life,” Weihl said.
Patients with all forms of SMA, which affects about one of every 6,000 babies born in the United States, are missing the SMN1 gene, which makes the survival motor neuron (SMN) protein.
This progressively weakens the muscles, leading to difficulty in walking, eating, clearing the air passageway and other essential functions.
Based on when the symptoms of SMA first manifest, physicians divide SMA into four subtypes. SMA I, for example, strikes very young children, causing weakness in the womb, preventing children from ever walking and typically resulting in death at an early age. Patients with SMA IV, in contrast, don’t develop weakness until adulthood. The seven patients studied were either SMA III or SMA IV, and ranged in age from 17 to 54.
Differences in age of SMA onset have been directly linked to a second human gene that also makes the SMN protein. That gene, SMN2, isn’t as efficient at making the SMN protein as SMN1.
Patients who develop SMA early in life have only one copy of the SMN2 gene in their DNA, leaving them with very low levels of the SMN protein. Patients who get the disorder later in life have more copies of the SMN2 gene, increasing the amount of SMN protein made in their cells and delaying onset.
“Because we have learned so much about SMA over the last decade, there’s been a big push at the National Institutes of Health (NIH) to cure this disease,” Weihl said. “The search has been on to find a treatment that can increase the amount of SMN2 protein synthesized by SMN2 genes. This rapid bench-to-bedside transition for valproate is a good example of the kind of progress that is encouraged both by NIH and the University’s Biomed 21 initiative.