MicroRNAs isolated from the bloodstream of patients with infant-onset spinal muscular atrophy (SMA) type 1 before treatment were related to functional responses to Spinraza (nusinersen) after six months of therapy, a study suggested.
Researchers said these microRNAs may be potential biomarkers to predict or monitor patients’ responses to treatment — which can vary widely, and range from “the absence of response to impressive acquisition of motor milestones and survival.”
“It is important to understand both the causes leading to the variable response as well as to identify biomarkers that could predict or monitor the response to treatment at an early stage,” the scientists wrote.
The study, “Response of plasma microRNAs to nusinersen treatment in patients with SMA,” was published in the Annals of Clinical and Translational Neurology.
In this rare genetic condition, abnormally low levels of the SMN protein in nerve cells cause progressive muscle weakness and atrophy (shrinkage), mainly affecting motor function. The SMN protein is present in virtually every cell in the body, and helps maintain protein balance.
Spinraza is an approved SMA therapy designed to increase the levels of SMN in cells.
Although Spinraza treatment has dramatically changed the natural course of the disease for some patients with infantile-onset SMA type 1, others have had a more limited response. Factors such as disease severity and the time between onset and treatment play a role in Spinraza’s efficacy, but they do not account for all clinical responses.
Therefore, researchers say, it is essential to identify biomarkers that can help better understand the factors that determine a patient’s response to Spinraza.
MicroRNAs — or miRNAs for short — are small segments of RNA that regulate gene expression (activity). They are emerging as biomarkers for disease diagnosis and progression, as well as treatment responses.
A study recently reported that certain miRNAs predicted Spinraza responses in a group of patients with later-onset forms of the rare genetic disease — to include SMA type 2 and SMA type 3. These miRNAs were associated with muscle cells found in the cerebrospinal fluid (CSF), the liquid surrounding the spinal cord and brain.
Now, researchers based at University College London, in the U.K., investigated whether miRNAs in the bloodstream could be biomarkers for Spinraza response in those with SMA type 1.
First, to identify microRNAs specific to SMA, the team obtained blood samples from 10 people with later-onset SMA type 2 and 10 with SMA type 3, who had not been treated with Spinraza, and seven healthy controls.
A total of 42 microRNAs were identified, of which 14 were at higher levels (upregulated) in SMA patients than controls, and 28 were lower (downregulated). An additional 27 differentially expressed microRNAs were found when comparing SMA type 2 and type 3 patients. However, these did not pass the significance threshold for multiple testing.
To find a connection between these 69 SMA-specific miRNAs and therapeutic response to Spinraza, blood samples were collected from 22 SMA type 1 patients given the therapy. The samples were taken at the first administration of Spinraza, then at two and six months of treatment.
The mean age of diagnosis among this patient group was 3.6 months, with treatment starting at a median age of 19 months, or just older than 1.5 years.
At each visit, participants underwent physical assessments using the Hammersmith Infant Neurological Examination Section 2 (HINE-2) and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). A larger difference in test scores indicated a better response to treatment, which was compared with pre-treatment (baseline) microRNA levels.
The baseline levels of six microRNAs — miR-107, miR-142-5p, miR-328-3p, miR-335-5p, miR-423-3p, and miR-660-5p — were significantly related to a Spinraza response at two and six months of treatment using CHOP-INTEND as an outcome measure.
Using HINE, the baseline levels of three microRNAs — miR-181b-5p, miR-125a-5p, and miR-23a-3p — were significantly related to treatment response at two and six months. The baseline level of miR-378a-3p was related to a HINE response at two months but not six months.
When the team compared the levels of microRNAs at two months with a change of CHOP-INTEND scores after six months of Spinraza, nine microRNAs correlated with the functional improvements. In particular, miR-142-5p and miR-378a-3p showed the highest prediction potential.
The team noted that many of these microRNAs are involved in signaling pathways related to the regulation of cell survival, cellular component recycling or autophagy, and programmed cell death known as apoptosis.
Although most participants were first treated between 1 month and 1.6 years of age, six began Spinraza between 2.3 and 4.3 years, and four patients were older than 10 years.
However, a comparison between the age at the start of treatment and the baseline levels of the most promising microRNAs overall did not detect any significant associations. The single exception was miR-107, which was higher in older patients.
“This result indicates that while most of the microRNAs identified in this study are stable with age, the impact of age on the levels of miR-107 should be considered when using miR-107 as a biomarker in SMA,” the researchers wrote.
A final set of experiments was conducted to determine whether Spinraza treatment affected the blood levels of 41 SMA-specific microRNAs. Compared with baseline, miR-335-5p and miR-328-3p were higher at two months, and miR-335-5p, miR-423-3p, and miR-142-5p were elevated at six months.
Among these five miRNAs affected by Spinraza, there was no connection between patients with a good response — CHOP-INTEND score improvement of at least two points or HINE score change of at least one point — and those with a poor response. There also was no significant correlation between the age and the baseline levels of these five miRNAs.
“We have identified a set of microRNAs in the blood of [Spinraza]-treated SMA patients that could be considered as potential biomarkers to predict or monitor patients’ response to treatment,” the researchers concluded.
“To further develop microRNAs in blood as biomarkers for SMA, more longitudinal [over time] studies in larger SMA [patient groups] will be needed to better understand the correlation of the microRNAs to disease progression and the improvement in motor function acquisition following different therapeutic interventions,” the researchers added.
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