microRNAs Possible Blood Markers of Children’s Response to SMA Therapies, Study Suggests

Muscle-specific microRNAs, small DNA-related molecules detectable in blood tests, may be biomarkers of disease progression and response to therapy in children with spinal muscular atrophy (SMA), a small study suggests.

The levels of several muscle microRNAs (miRNAs) in children with SMA type 2 and type 3 were lower after treatment with Biogen’s Spinraza (nusinersen). A sharp decline in one of them, miR-133a, correlated with physical improvements and may predict a favorable response to the therapy, the researchers said.

The study, “Circulating MyomiRs as Potential Biomarkers to Monitor Response to Nusinersen in Pediatric SMA Patients,” was published in the journal Biomedicines.

As new therapies for SMA emerge, an important medical need is the identification of non-invasive biomarkers that can help doctors monitor disease progression and anticipate patients’ response to treatment.

Spinraza, the first targeted therapy for children and adults with SMA, was approved by the U.S. Food and Drug Administration in 2016, followed by Zolgensma (onasemnogene abeparvovec-xioi by Avexis and Novartis) in mid-2019. Small molecules including risdiplam and branaplam are currently in clinical trials and may soon be available to patients.

So far, only phosphorylated neurofilament heavy subunit (pNF-H) — a major component of motor nerve cells — has been identified as a promising marker of SMA nerve cell damage and death (neurodegeneration) in children. Neurofilament, however, is not a tracer of muscle health.

Muscle weakness is one of the most prominent symptoms of SMA, so monitoring muscle health could help to track whether patients are responding well to therapies.

The small DNA-related molecules known as miRNAs have been increasingly viewed as diagnostic and prognostic biomarkers for neuromuscular diseases. They are easy to detect, they’re stable in body fluids, and their levels reflect altered cell functioning or damage of specific tissues.

miRNAs regulate the activity of many genes, and take part in different biological processes involved in the development of neuromuscular diseases like SMA. In fact, miRNAs are considered some of the most promising SMA biomarkers because survival motor neuron (SMN) protein — a deficiency of which causes most cases of SMA — plays an important role in their formation.

Researchers from Fondazione IRCCS Istituto Neurologico Carlo Besta in Italy investigated whether miRNAs, specifically those produced by muscles, could serve as biomarkers for clinical use to monitor disease progression and response to therapy in children with SMA.

They collected blood samples of 21 infants with SMA, with a median age of 5 (16 with SMA type 2, and five with SMA type 3) just before the first infusion of Spinraza and six months after treatment, to quantify the levels of muscle-specific miRNAs, also known as myomiRs, namely miR-133a, miR-133b, miR-206, and miR-1.

Pre- and post-Spinraza miRNA values were compared to each child’s response to therapy, assessed by how their physical abilities improved or worsened as rated by the Hammersmith Functional Motor Scale Expanded (HFMSE).

Six months after Spinraza dosing, 11 children had clinically meaningful improvement (defined as an increase in HFMSE of 3 or more points), seven children experienced smaller improvements, one child did not change, and two saw their conditions worsen.

The blood levels of three of the four miRNAs tested — miR-133a, miR-133b and miR-1 — were lower after six months of Spinraza therapy than prior to treatment in all patients.

A steep reduction in miR-133a was associated with a significant improvement in patients’ motor abilities, suggesting that “miR-133a reduction predicted patients’ response to therapy,” the researchers said.

“We thus propose circulating myomiRs, particularly miR-133a, as possible non-invasive biomarkers of therapeutic effect of nusinersen in SMA patients,” they said.

While more data from SMA patients will be necessary to establish muscle-specific miRNAs as biomarkers valuable for clinical use, the overall findings support their relevance as markers of neuromuscular disorders, “and support their potential as non-invasive biomarkers to monitor disease progression and measure the effectiveness of therapeutic interventions in SMA,” the researchers said.