Nusinersen Elicits Functional Innervation in Patients With SMA

According to the researchers, the findings are paving the way toward precision medicine and may have broader use in tracking treatment response in adult-onset motor neuropathy in the future.

A recent study adds to the literature on the benefit of nusinersen in spinal muscular atrophy (SMA), offering evidence of the treatment’s physiological impact for patients. According to the researchers, the findings are paving the way toward precision medicine and later down the line may have broader use in tracking treatment response in adult-onset motor neuropathy.

This study is the first to assess the usefulness of using 5 parameters of the Muscle Scan—a novel motor unit number estimation technique—to characterize the basis, timing, and extent of motor unit changes in SMN repletion therapy, finding that nusinersen stops disease-related axonal loss, thus altering the degenerative electrophysiological trajectory established on treatment-naïve patients.

Compared with the well-documented clinical response associated with nusinersen, data on the physiological effects of SMN repletion at the motor unit level is sparse. According to the researchers of the study, “This lack of biomechanistic knowledge is a rate limiting factor for development of therapeutic biomarkers and the evolution of therapeutics that may harness the motor unit’s ability to remodel, both of which impede the optimization of clinical outcomes for affected individuals.”

Throughout the study, 20 patients with SMA received treatment with nusinersen. The researchers found that the treatment was both an independent and significant driver of increases in 3 parameters: compound muscle action potential (CMAP) (P = .005), motor unit number estimation (MUNE) (P = .001), and motor unit number contributing to 50%–100% of CMAP (P = .04). These new findings also showed that increases were more pronounced in those with shorter disease durations.

For the remaining 2 parameters—largest single motor unit potential (P = .99) and amplitude of the smallest unit contributing to N50 (P = .77)—there was no change in the extent of compensatory collateral reinnervation.

“The study uniquely denotes that motor unit number increases soon after therapeutic induction,” wrote the researchers, noting that MUNE was the first parameter to show significant changes, which occurred after 6 months of treatment, which continued without plateau throughout the duration of the study. They added, “Electrophysiological measures correlate with functional change, highlighting the capacity of MUNE measures to act as biomarkers of therapeutic response.”

There was a significant increase in CMAP between the start of treatment and 18 months of treatment.

Prior to treatment, 5 children (25%) were non-sitters, 13 (65%) were sitters and 2 (10%) walked either independently or with support. Those who had higher disease burden—measured by their functional status and SMA phenotype—had lower CMAP, MUNE, and N50, representing their higher levels of neuronal degeneration. According to the researchers, these findings are similar to those of natural history studies showing that increased levels of motor neuron loss in patients with SMA type 1. The findings also suggest associations between neuronal loss and motor function.

Reference

Kariyawasam D, D’Silva A, Howells J, et al. Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen. J Neurol Neurosurg Psychiatry. 2021;92:78-85. doi:10.1136/jnnp-2020-324254