MDA-funded researchers say SMN, which is deficient in spinal muscular atrophy, is most needed during early life and in skeletal muscle and nerve tissues
Raising levels of the SMN protein, which is deficient in patients with the most common form of spinal muscular atrophy (SMA), has been the holy grail of therapy for this disease since the 1990s and is the goal of several experimental compounds now in development. (MDA-supported ISIS-SMNRx and RG3039 are examples.)
However, neither the timing of requirements for the SMN protein nor the tissues that most need it have been clear.
Now, MDA grantee Umrao Monani at Columbia University Medical Center in New York, with colleagues there as well as in Spain and Italy, have conducted mouse studies that shed new light on these questions. The team published its findings in the February issue of the Journal of Clinical Investigation; the paper can be read without charge on the journal's website.
By studying mice in which SMN production could be turned off at distinct time points, the investigators found that the requirement for SMN protein is critical until the connections between nerve and muscle (neuromuscular junctions) are fully formed and then becomes less important except when injuries occur or during the degeneration process that occurs in old age. Repairing aged or injured junctions temporarily increases the demand for SMN, an observation that could be translated into pulse dosing with SMN-elevating drugs in adult patients, Monani said.
In mice, the neuromuscular junctions are complete at 15 to 20 days of age; in humans, it is thought that the process extends through at least the first few years of life.
After that, the need for SMN drops precipitously, although higher levels are required if nerves or muscles are injured, and requirements increase to stave off age-related degeneration in elderly animals. The researchers believe the same is likely true in humans.
Also, by examining the effects of acute SMN depletion on different tissues, the investigators found that high levels of protein are required only by nerve fibers and skeletal muscles, not by the heart or by surface wounds, as some experts had previously suspected it might be.
"Future treatment to raise SMN levels may not have to be chronic," Monani said, "which is an important discovery, given the often adverse off-target effects of many drugs. We envisage a future SMN-enhancing treatment for SMA that is most intensely needed during infancy and childhood. Once the neuromuscular junctions mature, we expect that the patient will be able to tolerate low SMN protein much better, without experiencing acute disease. Not only does this tell us something important about the basic biology of the disease but also impact future therapeutic strategies."