Amplifying Copy Numbers to Reduce SMA Severity

Spinal muscular atrophy (SMA) is a collection of different muscle diseases characterized by the selective loss of motor neurons in the spinal cord. Grouped together, SMA is the second leading cause of neuromuscular disease and is the leading genetic cause of death in infants and toddlers. Much like DMD, SMA is caused by a mutated gene, in this case the “survival of motor neurons” (SMN) gene.  Techniques that increase expression of SMN from the existing SMN gene are a target of therapeutic efforts in spinal muscular atrophy.

“In humans, the SMN gene is duplicated,” said Arthur Burghes, PhD, professor of molecular and cellular biochemistry at The Ohio State University and Muscle Group member. “Spinal muscular atrophy results when SMN1 is lost, but SMN2 remains intact.”   While SMA patients are missing one version of the SMN gene, the number of SMN2 genes they have may vary. 

In a 2009 study, Muscle Group members examined the SMN2 copy number of adult SMA patients to compare the difference in those with three copies of the gene versus four copies.  They found that patients with three copies had an earlier age of SMA onset.  They had lower spinal muscular atrophy functional rating scale scores and were more likely to be non-ambulatory. There was, however, no difference between the groups in quantitative muscle strength or pulmonary function testing.

“These data suggest that compounds that increase the expression of SMN2 could be potential therapeutics for SMA,” said Dr. Burghes. “They also provide information that could be helpful when designing clinical trials since they show that functional scale may be a more discriminating measure of SMA status than muscle strength or pulmonary function.”

Muscle Group studies are also shining light on just how low levels of SMN affect motor neurons, primarily by examining a zebrafish model in which SMN protein levels were knocked down. “Our studies show for the first time in an animal model that SMN plays a role in motor axon development,” said Christine Beattie, PhD, associate professor in OSU’s Center for Molecular Neurobiology and Muscle Group member. “This suggests that these early developmental defects may lead to subsequent motor neuron loss as is seen in spinal muscular atrophy.”

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