The study, “Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients,” was published in the European Journal of Neurology.
SMA is characterized by abnormally low levels of the SMA protein caused by defects in the SMN1 gene. Disease onset and severity are dictated mainly by the production of SMN by a second SMN2 gene.
Spinraza is an approved SMA therapy designed to improve the function of SMN2 and increase the levels of SMN. It is most effective in those with SMA type 1, also called infantile-onset SMA, dramatically changing the disease’s natural history.
However, its efficacy in patients with later-onset forms of SMA, including types 2 and 3, is more variable, with about 40% of those treated with Spinraza showing a clinically meaningful response. Therefore, identifying biomarkers that predict treatment response in this population is needed.
A group of scientists based at the Weizmann Institute of Science in Israel, whose research focuses on microRNAs (miRNAs) — small segments of RNA that play essential roles in regulating gene expression (activity) — investigated these molecules as potential biomarkers for Spinraza response.
The team recruited 45 people with either SMA type 2 or 3 who received five Spinraza doses over six months. Cerebrospinal fluid (CSF), the liquid surrounding the spinal cord and brain, was collected before (baseline) and after the six-month period. Genetic analysis was applied to identify different miRNAs.
Motor function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). Individuals with an improved HFMSE score of three or more points were classified as responders, while participants with a score of zero or less were defined as nonresponders. Data from 11 patients with an HFMSE change of one or two units were excluded from the primary analysis to best distinguish between those with and without a response.
Although five miRNAs were found to change more than 1.2 times over six months, these data suggested that treatment had only a minor effect on miRNA profiles.
However, an examination of baseline miRNA profiles identified two significantly different miRNAs between eventual responders and nonresponders: miR-103b was higher by 2.6 times, and miR-206 was lower by 1.8 times.
At the same time, other miRNAs that are known to be expressed in muscle cells (myomiRs), like miR-206, were also found at lower levels in responders at baseline: miR-1-3p was 1.4 times lower, miR-133a-3p was 1.6 times lower, and miR-133b was 2.2 times lower. The results were the same when the 11 participants with a partial response were included in the calculations.
Two other miRNAs, miR-1180-5p and miR-6849, were also lower at baseline in those who self-reported energy improvement after therapy, compared with those with no energy improvement.
Statistical analysis of the results showed that lower baseline levels of miR-206 were predictors of positive treatment response, as measured by a change in HFMSE score. After excluding disease duration and SMA type, miR-206 is still predicted to have a differential response to Spinraza.
“Taken together, these data suggest that myomiRs predict the response to [Spinraza] therapy, and the miR-206 levels at baseline may predict the response to the [Spinraza] therapy,” the team wrote.
Combining data from different miRNAs that were low at baseline found that miR-206 and miR-133a-3p levels improved the therapy response prediction capacity. Adding SMA type to the calculation improved the predictive ability even further, as did including the sex of the patient, “with males being less likely to respond to therapy,” the researchers noted. In contrast, age as a variable did not improve the findings.
When the 11 partial response patients were added, both miR-133a and miR-206 remained predictors alone or in combination, but with reduced accuracy.
Finally, for the 26 participants with one-year follow-up data, miR-133a miR-206 pre-treatment levels were consistent with the six-month analysis, “indicating that extremely high levels of myomiRs predict poor response to [Spinraza],” the researchers added.
“These novel findings have high clinical relevance and may prove useful in helping to design appropriate protocols intended to refine and improve treatment outcomes,” the researchers wrote. “CSF miRNAs may be used as means to determine whether or not to initiate treatment.”
However, “future studies should be performed in a bigger, ethnically-diverse, groups of patients,” they added.
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