Scientists at Washington University School of Medicine in St. Louis retrospectively reviewed results from off-label use of the drug valproate to treat seven adult spinal muscular atrophy (SMA) patients. Clinicians offered the drug to patients on the basis of research conducted elsewhere that showed the drug increased levels of a key protein in cell cultures.
"The treatment has been fairly successful," says 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, will appear in the August 8 issue of Neurology.
Weihl notes 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 underway elsewhere in pediatric patients who suffer from a different type of SMA that begins earlier in life. Weihl and his colleagues 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 says.
Patients with all forms of SMA, which affects approximately one of every 6,000 babies born in the U.S., 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 NIH to cure this disease," Weihl says. "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."
In addition to its use as an epilepsy treatment, valproate, which is sold under the brand name Depakote, has been used to treat bipolar disorder, migraine headaches and other neurological conditions. The drug's effects include increasing the number of times protein-building instructions are read from genes, which is the first step in creating copies of proteins like SMN.
As patients took the drug, clinicians regularly gave them a series of strength tests. When Weihl reviewed the data from those tests, he found patient strength had increased significantly over the course of eight to 15 months of treatment with the drug.
According to Weihl, simply increasing the strength of an SMA patient's cough might enable them to clear their lungs better and reduce incidence of pneumonia, the most common killer of patients with SMA III and IV.
Valproate's side effects can include weight gain, hair loss and acne. One patient stopped taking the drug because she was concerned about weight gain.
"Adding weight can be a problem in patients who are already weak, and it's certainly a legitimate reason to stop taking the drug, but overall we didn't see significant weight gains in patients taking the drug," Weihl says.
Weihl and his colleagues are continuing to follow the seven patients reviewed in the study, who are still taking a daily maintenance dose of the drug.
Weihl CC, Connolly AM and Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology, August 8, 2006.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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