Levels of NfL protein in blood can pinpoint nerve damage side effects

Checking neurofilament light chain levels less invasive way to detect damage

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Blood is shown in vials and in a pipette.

Measuring levels of neurofilament light chain (NfL) in the blood could be used to detect subtle nerve damage that may occur as a side effect of experimental treatments for diseases like spinal muscular atrophy (SMA).

That’s according to the study, “Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity,” published in Toxicologic PathologyThe work was funded by Novartis.

“Serum NfL collection allows a non-invasive and sensitive assay that can detect neurotoxic effects and can be used to monitor drug-induced neurotoxicity in preclinical and clinical trials,” the scientists wrote.

When researchers are developing new experimental treatments, ensuring the therapy is safe for patients is a top priority. As such, especially in the early stages of development, it’s necessary to have rigorous monitoring for potential side effects. But, extensive monitoring can be burdensome for patients in clinical trials, so researchers are frequently looking for easier ways to monitor for potential issues.

This study specifically focused on an experimental therapy called branaplam, which Novartis had been developing for SMA until 2021, when the company decided to pull the plug on the program.

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Peripheral nerve damage seen with branaplam

In a preclinical study done in dogs, it was noted that branaplam sometimes caused damage to peripheral nerves (the nerves outside the brain and spinal cord). To test for this kind of damage in people, it would normally be necessary to conduct detailed evaluations of nerve electrical activity or to collect nerve biopsies — procedures that can be difficult especially for young children.

Here scientists at Novartis and other companies tested whether measuring NfL in serum (the noncell portion of blood) might be an easier way to monitor for peripheral nerve damage associated with medications like branaplam. NfL is a structural protein inside of nerve fibers; when nerves are damaged, NfL can be released into the body’s fluids, so the protein is commonly used as a general marker of nerve damage.

For this study, scientists treated dogs with branaplam or pyridoxine, a chemical known to cause extensive peripheral nerve damage. Other dogs were given an inactive vehicle as a control.

The researchers routinely measured serum NfL levels, and they also conducted detailed assessments looking for signs of peripheral nerve damage.

Results showed that pyridoxine-treated dogs had extensive peripheral nerve damage as expected, and this damage was consistently accompanied by an increase in serum NfL levels.

For dogs treated with branaplam, some peripheral nerve damage was seen, but patterns of damage varied considerably amongst the individual animals — some branaplam-treated dogs showed only very mild damage, whereas other had more moderate damage. Notably, none of the dogs given branaplam exhibited obvious symptoms of nerve damage, which were seen in dogs given pyridoxine.

The researchers found that serum NfL levels didn’t consistently increase for branaplam-treated dogs with only mild peripheral nerve damage. However, when the dogs had more moderate amounts of damage, there was consistently a clear increase in serum NfL levels.

“All branaplam-treated animals that exhibited a moderate severity nerve fiber degeneration of peripheral nerves showed elevated NfL levels in serum,” the researchers concluded. “Furthermore, no neurological and electrophysiological changes were observed in these animals, indicating that serum NfL elevations may be more sensitive.”

These findings support the idea that measuring blood NfL levels could be a less burdensome way to monitor for peripheral nerve damage in early safety studies for experimental medications, they said.