Combining treatment modalities increases the levels of SMN protein and improves the pathophysiology of spinal muscular atrophy (SMA), according to a study conducted on a mouse model of the disease. This approach can “broaden the therapeutic range of current treatments,” said the authors of the study published in Human Molecular Genetics.

Current disease-modifying treatments for SMA focus on increasing the levels of functional SMN protein. However, this production can be variable from 1 individual to the other and the approach does not constitute a cure for the disease.

Previous research has shown that combining 2 therapeutic modalities, ie inducing the production of SMN and slowing down its degradation, may improve outcomes.

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Here, a team of researchers led by Barrington G Burnett, PhD, from the Uniformed Services University of the Health Sciences in Bethesda, Maryland assessed whether slowing down the degradation of SMN protein as well as correcting splicing defects in the SMN gene could increase the level of functional SMN protein and improve SMA phenotype using a mouse model of the disease.

Read more about disease-modifying treatments for SMA

The team showed that treating the animals with ML372, which inhibits the ubiquitination of SMN and therefore its degradation together with an antisense oligonucleotide that corrects the splicing of the SMN gene, increased the levels of SMN protein in cells grown in culture and in the animals.

The researchers also observed improved spinal cord, neuromuscular junction, and muscle pathology in animals treated with ML372 plus antisense oligonucleotide.

“Importantly, the combinatorial approach resulted in increased motor function and extended survival of SMA mice,” the team wrote. “Our results demonstrate that a combination of treatment modalities synergistically increases SMN levels and improves pathophysiology of SMA model mice over individual treatment.”


Dumas SA, Villalón E, Bergman EM, et al. A combinatorial approach increases SMN level in SMA model mice. Hum Mol Genet. 2022;14:ddac068. doi:10.1093/hmg/ddac068