MDA-supported researchers at the University of Ottawa and Ottawa Hospital Research Institute (OHRI) have identified a biological pathway that may prove useful in developing treatments for spinal muscular atrophy (SMA).
Most treatment development for this disease focuses on increasing the production or viability of a protein called SMN. However, the experimental treatment the Ottawa researchers tried takes a completely different approach, one that the researchers say could provide an addition or alternative to SMN enhancement.
About SMA molecular mechanisms
SMA is a disease that involves loss of muscle-controlling nerve cells (motor neurons) in the spinal cord, which leads to severe weakness or paralysis.
The molecular basis of the disease is a deficiency of a protein called SMN, which stands for "survival of motor neurons." The severity of the disease corresponds to the amount of SMN; the lower the SMN level, the more severe the disease tends to be.
Replacing the deficient SMN protein or causing cells to make more SMN protein is an important part of SMA therapy development. (See In Focus: Spinal Muscular Atrophy.)
But compensating for the loss of SMN without changing the SMN level is a new possibility.
About the new findings
MDA grantee Rashmi Kothary at OHRI and the University of Ottawa coordinated the research team, which published its findings online Feb. 16, 2010, in Human Molecular Genetics.
Kothary and colleagues built on earlier research showing that, in addition to the loss of motor neurons, abnormalities of the so-called neuromuscular junctions — the meeting points of nerve and muscle fibers — also are a feature of SMA and are a likely contributor to disease symptoms. They decided to see if they could improve the health of the neuromuscular junctions, regardless of SMN protein levels.
First, they showed that depletion of SMN leads to an increase in the activation of a protein called RHOA, followed by an increase in the activation of a protein called ROCK and a lack of stable, mature neuromuscular junctions.
They then found that, when they gave mice with SMN gene defects and an SMA-like disease a compound that blocks ROCK activity, the mice had better-looking neuromuscular junctions and larger muscle fibers than did their untreated counterparts, and that they survived much longer and moved around their cages much better than did the untreated rodents.
The mice in these experiments had approximately 15 percent of the normal level of SMN protein and generally die within one month of birth. The mice treated with a compound called Y27632, which blocks the ROCK protein, survived for at least three months after birth, with some surviving more than eight months. In addition, they were able to move around their cages much more easily than the untreated mice.
However, when they tried treating mice with a disease mimicking the most severe human form of SMA because it produces very little SMN protein, they found the Y27632 compound was not helpful. These mice normally don't live more than a week, leading the researchers to speculate that there wasn't enough of a window for Y27632 to have a positive effect on neuromuscular junctions.
Meaning for people with SMA
"The present work provides novel avenues for therapeutic approaches to treat this devastating disease," the researchers say.
They note that the beneficial effect of Y27632 in their SMA mice is not due to SMN "rescue" but to "biological rescue, bypassing the SMN defect altogether."
They also say that their work shows that the different severity levels of SMA, which correspond to different degrees of SMN deficiency, may require different treatments or combinations of treatments. "Indeed," they say, "it is most likely that for SMA, the 'one-size-fits-all' approach will not be tenable."