Therapy That Corrects SMn2 Gene in Spinal Muscular Atrophy Shows Promise

Viable treatments for SMA remain elusive. However, researchers have recently made a series of impressive discoveries in treating the disease while experimenting on mice. These early successes could eventually translate into human therapies that will come to positively treat the disease in the future.

A new study entitled “A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy” published in Molecular Therapy — Nucleic Acids demonstrates the in vivo efficacy short antisense-oligonucleotide (ASO) in ameliorating spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the survival motor neuron 1 (Smn1) gene. As SMN1 protein is essential for motor neuron survival, lack of SMN1 results in muscle weakness and atrophy. SMA is the leading genetic cause of death in children. In humans, there is a highly similar gene to Smn1, the SMn2 gene. SMN2 differs from SMn1 by a single nucleotide, however, through a process called alternative splicing, this difference leads to a less functional and rapidly degraded protein.

Recently, antisense-oligonucleotide (ASO)-based therapy was suggested as a potential, new therapeutic strategy to rescue SMA by correcting the splicing event on Smn2 gene, thus reestablishing a functional SMN2 protein. However, the efficacy of a short ASO (<10-mer) in vivo remained to be tested.

In this study, the authors tested the therapeutic efficacy of a short ASO, 8-mer ASO (3UP8i), in two severe models of SMA. In the most severe SMA model, the administration of 3UP8i resulted in modest efficacy. However, its effect was impaired when compared with administration of longer ASOs in the same model. In a less severe model of SMA, the authors observed that 3UP8i induced a highly significant increase in survival, accompanied by improved neuromuscular junction pathology and corrected cardiac dysfunction, such as bradyarrhythmia.

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Thus, the authors report the first therapeutic potential of short ASO in an animal model of a human disease. Notably, the authors highlighted the fact that 3UP8i did not trigger an inflammatory response, thereby reinforcing its therapeutical potential. However, further studies will determine 3UP8i ‘off-target effects’ specifically at higher concentrations. While here tested for SMA, the authors highlight the therapeutic potential of short ASO in other human diseases.