MDA Finding Suggests "Backup" Gene Could Treat SMA
Rapid Search for Compounds Begins Using First Animal Model
TUCSON, Ariz., Feb. 1, 2000 — Scientists funded by the Muscular Dystrophy Association have initiated an aggressive screening process of some 40,000 compounds, seeking a drug to activate a gene that could compensate for defects in another gene that causes spinal muscular atrophy. SMA is a group of neuromuscular diseases that destroy nerve cells in the spinal cord, leading to paralysis and death. Affecting adults, children and babies, SMA varies in progression from slow to rapid, and one form of SMA is the most common inherited cause of infant mortality.
The rapid screening follows on the heels of a landmark study involving the first animal model for SMA. In findings reported in the February issue of Human Molecular Genetics, MDA grantee Arthur H.M. Burghes, associate professor in the Ohio State University Department of Medical Biochemistry and Neurology, led a team of investigators that created a new mouse model for SMA in parallel with a group from Taiwan. Using this model, the OSU researchers prevented symptoms of SMA by fostering an eight-fold increase in a gene involved in the production of an essential muscle protein called the survival motor neuron (SMN).
"This elegant research represents a watershed opportunity," said Leon I. Charash, chairman of MDA's Medical Advisory Committee. "By rapidly testing drugs in this new animal model for SMA, we'll efficiently determine which might be most appropriate for human clinical trials."
Muscle degeneration in SMA is caused by an insufficient amount of the SMN protein present in motor neurons. Two nearly identical genes - SMN1 and SMN2 - produce the needed SMN protein in healthy muscle. In SMA, the SMN1 gene is either missing or mutated, and the SMN2 gene doesn't produce enough full-length protein to compensate for the loss of protein that should be manufactured by SMN1.
Unlike humans, mice only have one SMN gene. To more closely mimic the human situation, the MDA researchers created mice that lack the mouse SMN1 gene but have either one or eight copies of the human SMN2 gene.
The group found that the mice with only one copy of the SMN2 gene expressed disease symptoms similar to those seen in severe human SMA and died a few days after birth. Those with eight copies of the backup gene, however, appeared normal at 8 months of age.
"What this means," Burghes said, "is that the SMN2 gene can compensate for the loss of SMN1 if it's present in enough copies. So we could potentially correct this disease in humans if we could find a way to increase the activity of the SMN2 gene."
The group also examined and counted the nerve cells in the spinal cords of the affected mice. They found that, at birth, the mice appeared to be genetically normal.
"This is a really important point from the perspective of a preventative therapy," Burghes said. "The fact that the motor neurons are not lost until later in the disease process may give us a window of opportunity to begin a potential treatment before any nerve cells are irrevocably lost."
If a drug can be developed to treat the disease, Burghes envisions a neonatal screening process to detect infants at risk of developing the disease so that treatment could be started immediately.
A group of researchers led by Hsiu Mei Hsieh-Li of the Academia Sinica in Taiwan reported the creation of a similar mouse model in the journal Nature Genetics.
MDA is the nonprofit health agency dedicated to curing muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education. Recognized by the American Medical Association with a Lifetime Achievement Award "for significant and lasting contributions to the health and welfare of humanity," MDA maintains 230 hospital-affiliated clinics that offer families the best in care for progressive neuromuscular diseases.
MDA annually funds some 400 scientific teams worldwide. These investigators have made significant advances toward cures for several muscle-wasting diseases. They also have pioneered breakthroughs that may well lead to therapies for heart disease, cancer, AIDS, Alzheimer's, Huntington's, Parkinson's and cystic fibrosis.
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