Combining 2 SMA therapies boosts SMN protein production: Study
Combination treatment also minimized risks of off-target effects
Combining a low dose of risdiplam, the active ingredient in Evrysdi, with a therapy like Spinraza (nusinersen) boosted SMN protein production beyond what the individual treatments do in cells from spinal muscular atrophy (SMA) patients, a study shows.
The low-dose combination demonstrated synergistic benefits while minimizing the risk of off-target effects that cause adverse events at higher doses.
The findings “provide a strong incentive to develop a combined therapy for SMA using [two] approved therapies, [Spinraza] and [Evrysdi],” the study’s researchers wrote in “Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene,” which was published in Neuroscience Insights.
In SMA, mutations in the SMN1 gene result in the SMN protein being deficient. The protein is essential for motor neurons, the nerve cells that control movement, which slowly die off without sufficient SMN such that the electrical signaling from the nerves to muscles is disrupted, triggering muscle weakness and wasting.
Cells do have a “backup” SMN2 gene that encodes the protein. Generally, more SMN2 copies are associated with less severe SMA, but due to a slight difference in a protein-coding region of the SMN2 gene called exon 7, a shorter, less stable, and poorly functional SMN protein is made.
Spinraza and Evrysdi are approved therapies designed to correct the exon 7 defect in the SMN2 gene, thereby increasing SMN levels. Evrysdi is an oral small molecule, while Spinraza is an antisense oligonucleotide (ASO), an RNA-like molecule that also corrects the exon 7 defect, administered into the spinal canal.
Combining two therapies, boosting SMN production
Despite the demonstrated benefits of both therapies for improving muscle function and extending survival, especially with early treatment, some patients still don’t reach certain motor milestones. Increasing the doses may improve their effectiveness, but this can cause more side effects due to treatment-related off-target effects, which occur when a treatment affects something other than its intended target.
Scientists at Iowa State University tested the impact of combining a low dose of Evrysdi’s active ingredient, risdiplam, with branaplam, a discontinued investigational therapy with the same mechanism of action. In cell-based experiments, the combination boosted the therapeutic effect on the SMN2 gene while minimizing some off-target effects seen at higher doses.
Here, the researchers tested the effectiveness of combining a low-dose ASO-based molecule called Anti-N1, which corrects exon 7 like Spinraza with risdiplam or branaplam in cells from SMA patients.
Consistent with previous findings, high doses of risdiplam or branaplam fully corrected the SMN2 exon 7 defect, while low doses resulted in a partial correction. Similarly, a high ASO dose alone mostly corrected the gene and low doses showed partial effects.
When low concentrations of branaplam or risdiplam were combined with Anti-N1, the SMN2 exon 7 defect was almost completely corrected by “more than any of the single low-dose treatments,” said the researchers, who then tested the off-target effects of single and combination treatments. High doses led to more than twofold changes in the activity of other genes than low doses with risdiplam (3670 vs. 1), branaplam (229 vs. 3), and Anti-N1 (3655 vs. 1).
In comparison, low-dose Anti-N1 combined with risdiplam altered the activity of 25 genes by more than two times. Anti-N1 plus branaplam changed the activity of 14 genes to a similar degree.
“We conclude that the combination treatment of a [correcting] ASO with small compounds represents a promising strategy for achieving a high level of SMN expression while minimizing the risk of off-target effects,” the researchers wrote. “The stage is set for future studies in animal models of SMA and eventually in SMA patients.”
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