A team of Japanese researchers has identified a blood biomarker for amyotrophic lateral sclerosis (ALS) and a drug candidate that targets it. The study, published today in JCI Insight, reports that a compound already deemed safe in humans slowed motor decline in mouse models of the disease.
Linking Metabolism to ALS Progression
Current treatments for ALS can only partly slow the disease, highlighting the urgent need for more effective therapies. The condition is known for motor symptoms like muscle weakness and movement difficulties, but it also causes widespread metabolic changes, including abnormal lipid metabolism and weight loss. The relationship between these systemic changes and the disease’s progression has largely remained unclear.
Masahisa Katsuno, MD, professor of neurology at Nagoya University Graduate School of Medicine, led the work. “Through our reverse translational approach, beginning with patient blood analysis, we identified metabolic changes throughout the body,” Katsuno said. “Based on these findings, we explored new treatments and demonstrated that the potential drug is effective in both patient-derived iPS cells and animal models.”
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Katsuno’s team performed a metabolomics analysis on blood samples from 81 individuals with either fast- or slow-progressing ALS and 35 healthy controls. The analysis screened 867 metabolites. Among them, the researchers identified N-linoleoyl taurine as the molecule most effective at distinguishing between the three groups. This compound belongs to a class of lipid signaling molecules known as N-acyl taurines (NATs), which are part of the broader endocannabinoid system—a network of lipid molecules involved in regulating neuronal signaling.
Further experiments showed that NAT levels were higher in patients with the fast-progressing form of ALS compared to those with slow-progressing disease. Across both groups, higher NAT levels correlated with faster progression and shorter survival times, suggesting the molecule could serve as a biomarker for tracking the disease.
It is difficult to overstate the significance of metabolic markers in neurodegeneration. In many similar diseases, the body’s internal chemistry shifts long before physical symptoms appear, offering a window into what is happening inside the nervous system. Finding a stable blood marker that reliably predicts how fast a patient will decline changes the clinical picture from reactive treatment to predictive monitoring.
Testing a Potential Treatment
Using the biomarker as a guide, the researchers screened 29 compounds known to modulate metabolic pathways within the extended endocannabinoid system. The screen identified a drug candidate that showed effects in both cell and mouse models. The compound targets an enzyme responsible for breaking down NATs, thereby raising their levels in the body.
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Using the biomarker as a guide, the team screened 29 compounds known to modulate metabolic pathways within the extended endocannabinoid system. The screen identified a drug candidate that showed effects in both cell and mouse models. The compound targets an enzyme responsible for breaking down NATs, thereby raising their levels in the body.
Tests in mouse models showed the drug extended lifespan, improved muscle strength and movement, and helped preserve neurons in the spinal cord. Gene expression analysis revealed that the compound alters the activity of genes involved in neuron growth and function, while shifting microglia toward a more supportive, anti-inflammatory state. No effects were observed in healthy mice, indicating the compound’s benefits are specific to ALS.
Importantly, the drug candidate has already undergone safety testing in humans. This prior data could potentially pave the way for faster clinical development down the line. The researchers next plan to study larger patient groups to determine whether NAT levels can act as a biomarker of disease severity and treatment response. They will also continue evaluating the compound and other drugs that target NATs and the extended endocannabinoid system as potential ALS therapies.
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