Spinraza treatment normalizes activity of several genes in SMA
Changes may be used as indicator of early treatment response: Researchers
Treatment for 10 months with Spinraza (nusinersen) normalized the activity of 38 genes in adults with spinal muscular atrophy (SMA), a genetic study showed.
Among the normalized genes were those involved in immune signaling pathways — findings that are “in line with the potential of this therapy to mitigate the neuroinflammatory features of SMA,” the researchers wrote.
Moreover, the use of the therapy increased the activity of the so-called backup SMN2 gene, consistent with Spinraza’s mechanism of action. The researchers suggested these changes may be used as an indicator of early treatment response.
The team noted their study’s small size as a limitation, but said that, “if confirmed in a larger cohort, this data may lead to … [SMN2 gene activity] as [an] early indicator for [Spinraza] efficacy in adult SMA, which may be a valuable support for … clinical practice.”
The study, “An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen,” was published in the Journal of Molecular Neuroscience.
Investigating the impact of Spinraza treatment on mRNA and miRNA
SMA is caused by low levels of SMN — a protein essential for the health of nerve cells that control movement — due to mutations in the SMN1 gene.
Cells also have a second SMN2 gene that, due to a slight difference in its DNA sequence, only produces about 10% to 15% of SMN protein. This is due to alternative splicing, a natural process by which a single gene can give rise to multiple proteins.
To make a protein, the information in DNA is transcribed into a template molecule called messenger RNA, or mRNA. Mature mRNA is formed when segments of the genetic code called introns are removed, or spliced out, and the remaining protein-coding segments, called exons, are linked together. With alternative splicing, multiple mRNA templates from a gene lead to multiple proteins.
In SMN2, such a splicing event excludes exon 7 from mRNA, leading to the production of a shorter and less stable SMN protein.
Spinraza is a splice-modifying therapy that prevents exon 7 exclusion and allows more functional SMN protein to be made. Clinical trials have demonstrated that the treatment can slow the progressive muscle wasting and weakness that characterizes the disease, improve motor function, and extend survival.
However, only a few studies have reported Spinraza’s impact on other processes involved in the development of SMA. These include microRNAs, or miRNAs — small RNA segments that lower or halt gene expression (activity) and protein production, mainly by binding with mRNA.
In this study, a research team in Italy investigated the impact of Spinraza on mRNA and miRNA in a group of SMA adults. As a secondary goal, the scientists explored changes in mRNA/miRNA in the patients before treatment, compared with age-matched healthy controls, to add further information about the underlying mechanisms of SMA.
First, the team examined blood samples collected from 10 adults with either SMA type 2 or type 3 before and after 10 months of Spinraza treatment.
As predicted by Spinraza’s mechanism of action, the expression of SMN2 significantly increased over 10 months in all patients except for one whose SMN2 activity remained stable. Consistently, there was an increase in exon 7 in what researchers call almost all-time comparisons.
According to the team, changes in SMN2 may be an early indicator for Spinraza’s effectiveness in adult SMA.
Therapy may mitigate neuroinflammatory features of SMA
Before treatment, the team detected 19 miRNA molecules that were produced at significantly lower levels than controls (downregulated) and 20 miRNAs at higher levels (upregulated). Also, 125 mRNAs were upregulated, and 22 mRNA were downregulated in patients versus controls.
After 10 months of treatments, 10 of the 39 changes observed in miRNA and 38 of the 147 mRNA changes did not differ any longer. Normalized genes included TRADD and JUND, which belong to the signaling pathway of interleukin-17, a pro-inflammatory immune signaling protein. The team noted that this finding suggested that Spinraza may mitigate the neuroinflammatory features of SMA.
Other genes restored by Spinraza treatment coded for so-called zinc finger proteins (ZNF524, ZNF467, ZNF628, and ZNF579), which mainly interact with DNA and RNA and are known potential modifiers of SMA.
An analysis of interactions between upregulated miRNAs and downregulated mRNAs showed that the SMN1 gene mRNA was the target of miRNAs called miR-146a-5p. Researchers noted that this miRNA has been shown to be involved in the loss of nerve cells that cause SMA.
Several molecular pathways were also identified in SMA diseases, including NOTCH, NF-kappa B, and Toll-like receptors.
Notch plays a role in cell-to-cell communication and controls numerous cellular processes, including cell proliferation, differentiation, and cell death. NF-kappa B regulates multiple aspects of immune functions and serves as a mediator of inflammation. Lastly, Toll-like receptors are an essential family of receptors involved in the first-line defense system against microbes.
According to the scientists, further study is needed.
“We believe that combined miRNAs/mRNAs expression analysis may be crucial for a more comprehensive approach also in rare genetic diseases like SMA, in which the causative mutation is known but so far, the whole [disease-causing] mechanism still needs some clarification,” the researchers wrote.
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