NfL protein levels may be helpful biomarker for SMA children: Study
Changes in levels may show disease progression, monitor treatment responses
Levels of the neurofilament light protein, known as NfL — which serves as an indicator of neurodegeneration — may be a helpful biomarker for monitoring disease progression and treatment responses in children with spinal muscular atrophy (SMA), a new review study suggests.
Across six published studies, culled from more than 600 records reviewed, blood NfL levels generally were found to be elevated in SMA patients, particularly those with fewer copies of the SMN2 gene.
But these levels tended to drop quickly once SMA-targeted treatments were started, the researchers found, thus suggesting the use of the NfL protein as a monitoring tool.
“Based on the available literature, we can therefore recommend using NfL as a biomarker in SMA to monitor disease severity and treatment responses, particularly in young children,” the researchers wrote. The team noted, however, that more clinical and laboratory studies are needed to validate the biomarker.
The study, “Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges,” was published in the journal Clinical Chemistry and Laboratory Medicine.
Researchers cite need for more biomarkers in SMA
SMA is characterized by the progressive degeneration, due to a lack of a protein known as SMN, of the specialized nerve cells, or motor neurons, involved in muscle control. Disease-modifying therapies, known as DMTs, aim to slow disease progression by boosting SMN production.
There remains a need, however, for disease-associated biomarkers that can be used to better monitor a patient’s prognosis and responses to treatment.
Current biomarkers only indirectly reflect downstream SMA disease processes, such as muscle function. As such, they don’t directly monitor motor neuron degeneration. Thus, they’re not effective for monitoring disease progression and neurodegeneration over time, according to the researchers.
NfL is a protein found in neurons that’s released into the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, when the neurons are damaged. It’s emerged as a marker of neurodegeneration across several diseases, most of which mainly affect adult populations, such as multiple sclerosis or amyotrophic lateral sclerosis.
But such data are “relatively scarce” for diseases that impact pediatric populations, the researchers noted.
Still, the European Medicines Agency recently recognized the potential of the NfL protein as a promising biomarker for pediatric neurological diseases.
Consistently, some evidence suggests that NfL measured in the blood or CSF could indeed be a good biomarker of neurodegeneration in SMA.
The recent publication included a review of the function of NfL and its possible role as an SMA biomarker. Information was collected by reviewing data from previously published studies on the topic.
Altogether, these data indicated that NfL in the blood or CSF is consistently higher in children with neurological diseases compared with healthy children — and that this is particularly pronounced in pediatric SMA patients.
Among individuals with SMA, the protein’s levels were associated with an earlier disease onset and indicators of more severe disease. Specifically, levels were higher in patients who had fewer copies of the SMN2 gene, a so-called backup SMN-producing gene. More copies of SMN2 are typically associated with less severe disease in patients.
“The data consistently indicate significantly elevated NfL levels in children with SMA,” the researchers wrote.
NfL protein levels found to be higher in SMA children
Given that NfL is a “cross-disease biomarker,” it cannot be used to diagnose SMA, the researchers noted. Still, its correlation with the SMN2 copy number positions it as a possible marker of disease severity or prognosis.
Most studies that have looked at NfL protein levels in response to SMA therapies have mainly involved treatment with Spinraza (nusinersen). Those studies demonstrated that blood NfL levels decline after treatment starts. That was especially pronounced in patients with two or fewer SMN2 copies, where drops in NfL correlated with improvements in motor function.
A single study also showed that Spinraza followed by Zolgensma (onasemnogene abeparvovec) leads to NfL reductions.
“There is a need to evaluate and monitor the neurodevelopment and treatment response in children receiving SMA therapy other than [Spinraza] or combinations of the different therapies,” the researchers wrote.
NfL levels naturally vary with age. To interpret changes in these levels among children with SMA, it’s necessary to establish reference levels in neurologically healthy children — which the scientists aimed to do based on data from the previous studies.
Reference percentiles of NfL in neurologically healthy children provide a practical visualization tool to estimate the relative increase of [blood] NfL levels in young children with SMA.
The team observed that the amount of the NfL protein declined until about age 9 in healthy children, after which it tended to stabilize until age 18. For a subset of children with SMA on Spinraza, NfL levels seemed to decline over time to below or near the median for their age group.
“Therefore, these reference percentiles of NfL in neurologically healthy children provide a practical visualization tool to estimate the relative increase of serum NfL levels in young children with SMA,” the researchers wrote.
Still, larger studies will be needed to clinically validate these reference ranges in more diverse groups of neurologically healthy children.
The scientists emphasized that before adopting NfL as an SMA biomarker, additional research is still needed to understand its real-world prognostic value and the long-term trajectory of the protein’s levels in advanced stages of treated and untreated SMA.