Scientists ID array of biomarkers that could track ALS progression
Proteins in blood, spinal fluid may also help monitor treatment responses
Researchers in the U.S. and Europe have identified a number of novel blood and spinal fluid biomarkers that could help track amyotrophic lateral sclerosis (ALS) progression and monitor patient responses to therapeutic interventions, a new study reports.
Several of the proteins found altered in people with ALS versus healthy individuals — biomarkers that changed as the disease advanced — were linked to skeletal muscle biology. Other markers were associated with inflammation and immune activity, offering insights into the broader biological mechanisms of ALS.
“We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of [the] disease,” the researchers wrote.
Their study, “Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study,” was published in the journal Annals of Neurology.
ALS is caused by the progressive loss of motor neurons, the nerve cells that control voluntary movements. Treatments now available may slow disease progression, but none can halt or reverse the loss of these cells.
Researchers note ‘pressing need’ for biomarkers in ALS
Biomarkers, which detect biological signals of disease, are essential for advancing the development of new ALS therapies. By tracking disease progression and treatment response, such markers can improve trial design and accelerate the testing of new therapies. However, according to the researchers, available biomarkers in ALS remain limited.
“With increasing recognition of the essential role for biomarkers in Phase 2 [clinical] trials, there is a pressing need to identify additional biomarkers with utility in monitoring and demonstrating response to an experimental therapeutic,” the researchers wrote. Phase 2 trials typically involve a larger group of participants than earlier Phase 1 studies, which tend to focus on a treatment’s safety.
Now, a team from Novartis, which is developing therapies for neurodegenerative diseases, worked alongside researchers at the University of Miami Miller School of Medicine in Florida to identify new biomarkers for ALS. A total of 10 of the 17 scientists are Novartis employees, and two others serve as site investigators for company-sponsored trials.
The team compared protein profiles in blood and spinal fluid from both healthy volunteers, who served as controls, and people with ALS followed at the University of Miami as part of three major natural history studies.
Altogether, the analyses used blood samples from 157 ALS patients and 163 healthy controls, and spinal fluid samples from 70 ALS patients and 51 controls. For many participants, repeat samples were collected over time along with matched clinical data, providing a way to track changes in biomarker levels as the patients’ disease progressed.
Levels of TNNT2 nearly 3 times higher in ALS patients vs. volunteers
Using a panel that assessed about 7,000 proteins, the researchers identified 329 blood proteins that were significantly different in people with ALS compared with healthy volunteers. Of these, 132 were present at higher levels and 197 at lower levels.
Proteins involved in muscle structure and contraction, such as TNNT2, PDLIM3, and MYL11, were present at higher levels and tended to increase further as the disease advanced. By contrast, several proteins were found at lower levels in ALS than in healthy volunteers. These proteins — among them ANTXR2, CLEC3B, and ART3 — were shown to decline further with disease progression.
Most of these biomarker patterns appeared independent of treatment status, suggesting they mainly reflected the disease process rather than medication effects. The only exception was treatment with riluzole (sold as Tiglutik and generics), which increased levels of the protein KCNIP3.
In spinal fluid, 20 proteins were found to differ between the ALS patients and healthy volunteers. These primarily were neurofilament proteins, which are well-known markers of nerve damage, inflammatory proteins (CHIT1, GFAP, GPNMB), and the muscle protein MYL11.
These findings were validated in an independent group of patients and healthy volunteers, with those results showing similar overall patterns in both blood and spinal fluid.
Until now, there have been limited biofluid markers for ALS disease progression, which might be used as outcome measures in early phase clinical trials. … Our approach to biomarker discovery has identified … an array of novel candidates that change over time as the disease progresses.
Further testing then highlighted TNNT2 as one of the most promising candidates, according to the researchers. Levels of this muscle protein were nearly three times higher in the blood of ALS patients than in healthy controls and continued to rise steadily as the disease progressed. GPNMB in spinal fluid also emerged as a key marker, though it appeared more stable over time than TNNT2.
“Notwithstanding an incomplete understanding of the biological mechanism, our data suggest that [blood] TNNT2 could be considered in pharmacological clinical trials to monitor the possible effects of therapeutic interventions,” the researchers wrote.
This would help in assessing new treatment candidates, according to the team.
“Until now, there have been limited biofluid markers for ALS disease progression, which might be used as outcome measures in early phase clinical trials,” the researchers wrote. “Our approach to biomarker discovery has identified and replicated an array of novel candidates that change over time as the disease progresses.”
About the Author
