PRMT inhibitor alone or as Spinraza add-on shows promise
The molecule, a PRMT protein inhibitor called MS023, and Spinraza — both of which are able to boost production of the SMN protein that’s lacking in SMA — each extended survival and normalized abnormal gene activity. But together, the gains were even greater. These greater effects appeared to be mediated by the treatment combo’s ability to ease neuroinflammation.
“Our study warrants further clinical investigation of PRMT inhibition both as a stand-alone and add-on therapy for SMA,” the researchers wrote.
The study, “PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice,” was published in EMBO Molecular Medicine.
NfL may be biomarker of response to Spinraza in early stages of SMA
SMA is caused by mutations in the SMN1 gene, resulting in a lack of production of the SMN protein that is important for the health of nerve cells that control movement, leading to their degeneration.
There also is a so-called backup SMN-producing gene, SMN2. This gene encodes a shorter and more easily degraded version of the SMN protein than does SMN1. That’s because a specific protein-coding portion of the genetic code called exon 7 is cut out from the gene when it is being read to produce the protein.
The number of copies of the SMN2 gene a person has varies naturally and can influence disease outcomes significantly in SMA. More copies means more SMN production, and is associated with less-severe disease.
There are two approved SMA disease-modifying therapies that target SMN2 to increase its production of a full-length, exon 7-including version of SMN – Spinraza and Evrysdi (risdiplam).
Targeting processes that regulate gene activity
Another possible way of increasing SMN production that’s gained recent attention is to target natural epigenetic mechanisms, or biological processes that regulate gene activity, which influence SMN2’s production of the protein.
In their recent study, the scientists sought to identify epigenetic proteins that might serve this purpose for treating SMA.
In an SMA patient cell-based screen of 54 different molecules, the researchers identified one, MS023, that was able to promote exon 7 inclusion in SMN2’s pre-mRNA — an intermediate template molecule formed when a gene is being read to make protein — and increase SMN protein levels.
MS023 is an inhibitor of type 1 PRMTs, which are enzymes involved in an epigenetic mechanism that works to silence, or reduce the activity, of the genes that they bind with. Various families of PRMTs have been implicated in SMA.
The molecule promoted exon 7 inclusion by preventing binding between SMN2 and HNRNPA1, a molecule known to prevent exon 7’s inclusion.
Daily oral administration of MS023 in a mouse model of SMA led to significantly prolonged survival and prevented disease-associated weight loss. Moreover, an increase in SMN2 mRNA was observed in the skeletal muscles, and SMN protein levels were boosted in the spinal cord and skeletal muscles.
Next, the researchers examined whether combining MS023 with Spinraza might lead to even greater benefits in the mouse model. Mice were treated with a single dose of Spinraza — one lower than the established optimal dose — alone or in combination with daily MS023.
Enhancing exon 7 inclusion
The combined treatment was found to further enhance exon 7 inclusion in addition to increasing SMN protein levels in a variety of tissues. The duo also significantly prolonged lifespan from a median of 19.5 days with Spinraza alone to 97.5 days, in addition to increasing body weight.
“Overall, these results suggest that oral administration of MS023 synergises with nusinersen to provide a therapeutic benefit in SMA,” the researchers wrote.
In the SMA model, more than 5,000 genes were found to have dysregulated expression, or activity. MS023 treatment alone corrected 77.5% of them, Spinraza corrected 86.2%, and the combination corrected 88.9%.
Genes targeted by the combination therapy often were related to immune signaling pathways, “suggesting that targeting neuroinflammation for therapy is key to achieving a beneficial effect in SMA,” the researchers wrote.
Few genes unrelated to SMA (off-target) were affected by the treatments, suggesting a good safety profile.
“Altogether, these promising preclinical results warrant further clinical investigations of MS023 or other selective type I PRMTs inhibitors both as a stand-alone and as an add-on treatment with nusinersen in SMA patients,” the researchers concluded.
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