Neurofilament light chain (NfL) is a member of a family of proteins called neurofilaments that contribute to the structure of neurons in the brain and spinal cord. Research has shown that when neurons experience injury or damage, these proteins are shed and find their way into the cerebrospinal fluid (CSF) and bloodstream. While even healthy neurons shed a certain amount of NfL, elevated levels of the protein in blood or CSF are associated with several conditions that affect the central nervous system.
This has made NfL attractive to researchers as a potential biomarker in several diseases – including amyotrophic lateral sclerosis (ALS). A biomarker is a kind of biological “fingerprint” – something measurable about a living thing that can provide doctors or scientists with information about that organism. Biomarkers have many potential functions in diseases, including:
- Helping doctors diagnose a disease
- Measuring the progression of a disease
- Helping researchers see whether a drug has reached its intended target in the body
- Providing evidence that a drug is changing the course of a disease
Some common biomarkers associated with diseases include blood glucose levels for diabetes or LDL cholesterol for heart disease.
A lack of reliable biomarkers for ALS is one of the biggest challenges in this disease. For example, ALS diagnosis is based on the clinical presentation of symptoms combined with tests like EMGs, while eliminating other possible diagnoses. There is also much interest in developing and using biomarkers as surrogate endpoints in clinical trials. To date, ALS trials have generally relied on measuring a person’s survival, which can lead to lengthy trials, or changes in motor function through the ASLFRS-r survey, which has been criticized for not being sensitive or completely objective. As a surrogate endpoint, a biomarker would be used to show that a drug is having a reasonably likely effect on a disease.
The Potential of NfL in ALS
NfL is often called a nonspecific biomarker because it can increase not only in ALS, but in many other conditions, including traumatic brain injuries, multiple sclerosis, and Alzheimer’s disease. Because of this, NfL has limited potential as a diagnostic biomarker for ALS. However, an observed increase in the level of blood NfL has been found to be a potential indicator of the onset of ALS symptoms for people with ALS-related genetic mutations. It is showing promise as a biomarker for risk of onset of the disease in that subpopulation.
The level of NfL in the blood and CSF at diagnosis has been shown to correlate with the speed and severity of ALS progression, which has indicated that it may be a prognostic biomarker for ALS. While all people with ALS appear to have some degree of elevated NfL in earlier stages of the disease, those with higher NfL levels early on have been found to experience faster disease progression than those with lower NfL levels.
NfL in Clinical Trials
Currently, researchers are also focused on NfL’s potential as a biomarker of drug response in clinical trials. Because NfL is a structural component of neurons that is released when they are damaged, an experimental treatment that decreases levels of NfL in a clinical trial could indicate a possible slowing in neurodegeneration. This means that NfL has potential as a surrogate biomarker in ALS clinical trials.
In one recent case, Qalsody, a treatment for SOD1-related genetic ALS, was granted accelerated approval based on results demonstrating lowered levels of blood NfL in trial participants. A second trial of the drug for asymptomatic carriers of fast progressing SOD1 mutations is currently ongoing. This trial is also following participants’ NfL levels, in this case to determine when to start dosing the drug. A rise in NfL levels in asymptomatic carriers could indicate that the onset of weakness is likely approaching in the next 6-12 months. By administering the drug at this early time, researchers hope to delay the disease onset.
There is also currently interest in creating a platform trial to screen experimental treatments based on their effects on biomarkers, including NfL. The EXPERTS-ALS trial, which has been announced in the UK to begin in 2024, plans to use a platform trial design to screen drugs in a six-month phase 2 trial with no placebo. Researchers will evaluate levels of NfL and other biomarkers in this trial to determine whether drugs should move on to a phase 3 trial.
Searching for Other Biomarkers
Just like we know that it will certainly take many different drugs to end ALS for everyone with the disease, it will also likely take multiple biomarkers to accurately diagnose, track progression, and create more sensitive measures for clinical trials. At the ALS Therapy Development Institute (ALS TDI) we are working through our ALS Research Collaborative (ARC) program to partner with people with ALS all over the world to collect data and to search for potential biomarkers.
These efforts include our first-in-kind In-Home Blood Collection program, which allows ARC participants to contribute regular blood samples by mail without leaving their homes. By studying these samples over time, we aim to identify more potential blood-based biomarkers that could correlate to disease progression. In 2022, ALS TDI received a grant from the Department of Defense (DOD) to fund an expansion of this program, along with more advanced sample testing with the potential to reveal new protein biomarkers of ALS.
In addition to using biological samples, ARC researchers are working to use data to create digital biomarkers for tracking ALS progression. Some participants in the program are provided with digital accelerometers to be worn on the arms and legs to generate movement data and asked to periodically record voice messages to keep track of vocal function. In 2022, ALS TDI and our research partners at Google announced a new, machine learning-powered tool that is able to accurately predict a person’s ALSFRS-r by analyzing these voice recordings. A second paper, in 2023, published in partnership with researchers from Massachusetts General Hospital, used data from ARC to support the potential of accelerometers worn throughout the day as a measure of progression.
Anyone diagnosed with ALS, and asymptomatic carriers of ALS-related genetic mutations, can participate in the ARC study and help to contribute to this important research. To learn more about the ALS Research Collaborative, click here.
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