Jackson Laboratory researcher and collaborators propose new treatment approach to SMA

Date: August 9, 2011
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Bar Harbor, Maine—Jackson Laboratory Research Scientist Cat Lutz, Ph.D., and collaborators at Columbia University and other laboratories, have demonstrated a new approach to treating the devastating neuromuscular disease known as spinal muscular atrophy (SMA).

SMA is the most frequently inherited cause of infant mortality, affecting about four out of every 100,000 births. Infants experience progressively severe, and ultimately fatal, muscle degeneration and weakness.  The disease has been traced to mutations in the motor neuron (SMN1) gene that reduce levels of a protein known as SMN.

"It was clear that if we could restore levels of SMN protein in patients with SMA," Lutz said, "we could reduce the severity of the disease, but it was not clear exactly when SMN should be administered."

Lutz, working with Umrao R. Monani, Ph.D., and colleagues at Columbia University, and researchers at Regeneron Pharmaceuticals Inc. and The Spinal Muscular Atrophy Foundation, took on the challenge, developing a new mouse model of SMA. Their work was published in the August issue of the Journal of Clinical Investigation.

Lutz is associate director of The Jackson Laboratory's Genetic Resource Science Repository, which works to develop and provide the best mouse models of human diseases to the worldwide biomedical research community. "Our special model of SMA allowed us to investigate the effects of turning on SMN expression at different time points during the course of the disease," she explains. "We found that restoring the SMN protein even after disease symptoms appeared reversed the motor neuron degeneration."

The researchers also discovered that for the best effect, early administration of the SMN protein works best. "There was a therapeutic 'window of opportunity' during which the mice responded best to the SMN treatment," Lutz said. Mice treated later, after symptoms appeared, showed some improvement, but those treated after substantial neurodegeneration had already occurred failed to show therapeutic benefit.

In a commentary article published in the same issue of the Journal of Clinical Investigation, Kathryn J. Swoboda, M.D., of the University of Utah School of Medicine, noted, "In order to have the best chance for a 'cure,' or even definitive proof of a more modest benefit, we may have to target our early efforts to those with less severe disease, early in the clinical course.

"For that reason, a broader adoption of newborn screening for SMA may prove the most rapid and effective means of identifying a cohort of infants and children who represent the best candidates for promising therapeutic treatments in the near term. Ultimately this will benefit the greatest number of patients by allowing early qualification of promising therapies," Swoboda concluded.

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Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. Volume 121, Issue 8, J Clin Invest. 2011;121(8):3029–3041. doi:10.1172/JCI57291.

 

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