Scientists identify blood markers that may predict ALS progression

Two blood markers indicative of inflammation and cellular stress may help predict disease progression patterns and survival in people with amyotrophic lateral sclerosis (ALS), a study found.

Higher levels of these two markers, LBP and 4-HNE, “were correlated with a more rapid disease progression rate, shorter survival, and [worse disease severity] scores,” the researchers said.

“These findings raise the question of whether these biomarkers may be useful for monitoring the therapeutic slowing of disease progression,” they wrote in the study, “Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival,”  published in Annals of Clinical and Translational Neurology.

In ALS, the nerve cells that control movement gradually sicken and die, leading to muscle weakness and eventual paralysis. The causes of ALS are not fully understood, but several biological processes have been implicated in the disease.

For example, there’s evidence that atypical inflammation in the nervous system may contribute to nerve cell damage in ALS. Oxidative stress — a type of cell damage caused by excessive amounts of reactive oxygen-containing molecules — is also thought to help drive nerve damage in ALS. Whether these altered processes provide biomarkers to monitor disease progression and predict treatment response, however, remains an ongoing area of research.

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Predicting disease progression

Scientists at Houston Methodist Hospital analyzed levels of three blood biomarkers to assess their ability to predict disease progression and survival in people with ALS: lipopolysaccharide binding protein (LBP), a marker of inflammation, and 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress, as well as neurofilament light chain (NfL), a well-established marker of nerve damage linked to worse outcomes.

The team examined blood samples from 100 ALS patients and 100 age- and sex-matched controls without the disease. Results showed that average levels of all three blood biomarkers were higher in ALS patients than in people without the disease.

For LBP and 4-HNE, the markers of inflammation and oxidative stress, levels were elevated at the time of ALS diagnosis and continued to increase as the disease progressed. These trends “suggest that increasing systemic levels of [oxidative stress] and inflammation contribute to [underlying disease biology in ALS],” the researchers said, noting that blood levels of LBP and 4-HNE “are not increased in other neurodegenerative diseases such as [Parkinson’s and Alzheimer’s disease].”

NfL, the marker of nerve damage, showed a different trend: Levels were elevated at the time of ALS diagnosis, but increased only modestly through the last sample, indicating NfL levels reached a plateau as the disease progressed.

Statistical analyses showed that all three biomarkers were significantly associated with survival and disease progression rates. LBP and 4-HNE showed stronger associations than NfL. Still, models predicting survival and disease progression were most accurate when all three biomarkers were used.

“These findings suggest the potential utility of integrating 4-HNE, LBP, and NfL to improve discrimination of clinical ALS outcomes and highlight their complementary contributions to [underlying disease biology in ALS],” the researchers wrote.

The study was funded in part by Coya Therapeutics, which is developing an experimental ALS therapy that contains a combination of interleukin-2 (IL-2) and CTLA4-Ig, two molecules that act to dampen inflammation.

An early clinical study of the therapy, COYA 302, in ALS patients indicated that it reduced LBP and 4-HNE levels, which suggests it may slow disease progression and extend survival, according to a company press release.

The small, proof-of-concept Phase 1 clinical trial (NCT06307301) showed stable ALS Functional Rating Scale (ALSFRS-R) scores after nearly one year of treatment, with one patient showing an improvement in their ability to perform daily tasks.

“These findings demonstrate significant correlations between biomarkers of inflammation, oxidative stress, and [nerve] injury and survival in patients with ALS,” said Fred Grossman, Coya’s president and chief medical officer.

Coya is sponsoring a Phase 2 study, ALSTARS (NCT07161999), testing COYA 302 against a placebo in about 120 adults with sporadic or familial ALS. The main goal is to confirm whether the therapy can significantly slow ALSFRS-R decline over six months.

“In our ongoing ALSTARS trial, we are measuring NfL as a secondary endpoint, along with inflammation markers including 4-HNE and ox-LDL as exploratory endpoints,” he said. “Together, these efforts will further inform the growing body of evidence supporting the role of inflammation in neurodegenerative diseases.”