Research progress in spinal muscular atrophy (SMA) has been considerable in recent months.
Some 95 percent of people with this disorder of the muscle-controlling nerve cells of the spinal cord (lower motor neurons) have mutations in both copies of a gene on chromosome 5 known as SMN1, which normally makes the protein SMN (survival of motor neurons). But all people with SMA have at least two copies of a neighboring gene called SMN2, which makes some of the same SMN protein as the SMN1 gene normally does but mostly makes a shortened version of SMN.
The more copies of the SMN2 gene a person has, the less severe the effects of SMN1 mutations generally are. The most severe form of SMA, generally fatal in early childhood, is called type 1. An intermediate severity form is called type 2, and the least severe, chronic form is type 3.
The majority of SMA treatment strategies are based on increasing output of full-length SMN protein molecules from SMN2 genes, which everyone with SMA has.
A rare form of SMA is related to defects in an X chromosome gene that hasn’t yet been identified. This form is similar to the chromosome 5 SMA type 1.
Phenylbutyrate trial disappointing
A trial of phenylbutyrate (PB), a compound that in laboratory studies has increased cellular production of SMN, has failed to benefit children with type 2 spinal muscular atrophy (SMA2), say researchers at 10 centers in Italy, who conducted the trial.
Eugenio Mercuri at Catholic University in Rome, and colleagues, studied 107 children with SMA2 who were between 2 and 12 years old, randomly assigning them to receive either PB or a placebo for 13 weeks. Neither participants nor investigators knew which children were getting PB and which the placebo until the study was completed. After 13 weeks, the PB-treated children and the placebo-treated children had similar motor function test scores, the researchers reported in the Jan. 2 issue of Neurology.
The lack of difference in the two groups may, they say, be related to the short study duration and the dosing schedule, which was seven days on/seven days off. They say an altered schedule and longer exposure to PB might produce different results.
“[These results] don’t diminish our enthusiasm for pursuing additional studies on phenylbutyrate for two reasons,” says Kathryn Swoboda at the University of Utah, who’s conducting a trial of PB in SMA in the United States.
“One, the treatment duration of 13 weeks in this study was extremely short, and I wouldn’t necessarily have expected any significant effect with treatment for that duration of time for a medication expected to work on motor neurons [nerve cells].
“Two, the regimen used for treatment in this study involved a dosing schedule in which, on alternate weeks, children weren’t taking any medication. We’re encouraged by the enthusiasm of the Italian SMA community in bringing this trial to rapid fruition.”
Trials of PB in children with types 1, 2 and 3 SMA, sponsored by the National Institutes of Health, are slated to begin this spring.
For updated information, see MDA's clinical trials section online.
HDAC inhibitor benefits mice
An experimental compound called trichostatin (TSA) can increase the amount of SMN protein in mice with SMA and shows promise for the treatment of the human disease.
When U.S. and Italian scientists, including MDA-supported Livio Pellizzoni at Dulbecco Telethon Institute of Cell Biology in Rome, gave TSA to mice with SMA, they saw 1.5-fold to twofold increases in total SMN protein levels in the brain, spinal cord and liver. They also saw healthier muscle and nerve cells, as well as significant improvement in the motor function and survival in three-quarters of the mice. About one-quarter didn’t respond to the drug.
These improvements occurred even though the mice were very weak when they started TSA therapy. In their paper, published online Feb. 22 in the Journal of Clinical Investigation, the researchers say this response bodes well for treatment of humans, since SMA is rarely diagnosed before weakness becomes evident. However, they also say that earlier intervention might be even more effective.
TSA belongs to a family of chemical compounds called HDAC inhibitors, which cause cells to interpret genetic instructions as “open” and ready to be read, rather than “closed” and silent.
Theoretically, TSA increases the amount of time that SMN2 genes are open for production of SMN protein molecules. SMN2 genes, which all SMA patients have, normally lead to production of a very small amount of full-length SMN protein and can only partially compensate for the loss of SMN1 gene function that is SMA’s underlying cause.
The researchers say their results provide a strong basis for examining HDAC inhibitors in clinical trials in SMA. TSA itself hasn’t been approved for clinical use, they note, but it probably could be developed for that.
Other HDAC inhibitors are in clinical trials for other diseases, and one has been approved by the U.S. Food and Drug Administration for treatment of lymphoma.
“In the future,” said Pellizzoni, “the use of HDAC inhibitors, in combination with other types of compounds that stimulate the levels (or activity) of the SMN protein, might be an attractive treatment strategy for this disease.”
SMN1 vs. SMN2 gene instructions
Investigators at Columbia University in New York and the University of California-Berkeley report a significant addition to the understanding of the differences in protein output between the SMN1 and SMN2 genes.
Tsuyoshi Kashima at UC Berkeley, and colleagues, writing in the Feb. 27 issue of Proceedings of the National Academy of Sciences, describe how two differences — one they previously identified and one new one — combine to cause the SMN2 gene to leave a sequence called exon 7 out of the final instructions for the SMN protein. Complete instructions for the full-length protein are in the “rough draft” instructions.
The omission of exon 7 from the final genetic blueprint means that most of the protein produced from the SMN2 gene is shorter than that produced from the SMN1 gene.
“Our data has provided evidence that a second rare ... difference between SMN1 and SMN2 contributes to SMN2 exon 7 exclusion,” the researchers write.
The more information scientists have about why exon 7 is excluded from SMN2 instructions, the better equipped they’ll be to coax its inclusion and production of full-length SMN protein from this gene.
SMA can be X-linked
MDA grantee Lisa Baumbach-Reardon at the University of Miami’s Miller School of Medicine, with colleagues in the United States, Spain and Germany, can now say with assurance that there is an X-linked form of SMA that resembles the most severe (type 1) chromosome 5 form. X-linked diseases generally affect only males, but females can be carriers.
In the January issue of Genetics in Medicine, the investigators describe eight families (one previously analyzed and the other seven new to this study) with an X-linked disease affecting only male infants and involving severe loss of muscle tone, as well as multiple contractures (frozen joints) and/or bone fractures. Death occurred within the first two years of life in 75 percent of cases.
The investigators note that an X-linked disease resembling severe infantile SMA was first described in 1938, but the disorder has been presumed rare. They say their new findings, coupled with the approximately 4 percent of SMA patients who don’t appear to have SMN1 mutations, may mean that X-linked SMA isn’t as rare as has been presumed.
They’ve determined that X-linked SMA, like its chromosome 5 counterpart, is primarily a disease involving loss of lower motor neurons. Finding another SMA gene, they say, “will provide major insights ... into the etiology [origin] and developmental timing of motor neuron loss,” with implications for all types of SMA.