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| Image Credit: Daisuke Ito (modified from Ito et al., JCI Insight, 2026 (CC BY 4.0) |
Scientific Frontline: Extended "At a Glance" Summary: PF-04457845 and ALS Progression
The Core Concept: Researchers have identified a metabolic marker in the blood, N-acyl taurines (NATs), that correlates with the progression of amyotrophic lateral sclerosis (ALS), and they found that a compound named PF-04457845, which boosts NAT levels, slows motor decline in mouse models of the disease.
Key Distinction/Mechanism: While most ALS research relies on mouse models mimicking inherited forms of the disease or patient-derived induced pluripotent stem (iPS) cells, this study began by analyzing the blood of human patients to identify metabolic changes across the body. The researchers discovered that PF-04457845 works by blocking an enzyme that breaks down NATs, thereby preserving higher levels of NATs, which appear to protect nerve cells and shift spinal cord immune cells (microglia) toward a supportive, anti-inflammatory state.
Origin/History: The study was conducted by a team led by Professor Masahisa Katsuno and Assistant Professor Daisuke Ito at Nagoya University Graduate School of Medicine, along with researchers from Aichi Medical University and Juntendo University. The findings were published in JCI Insight in 2026.
Major Frameworks/Components:
- Metabolite Screening: The team screened 867 metabolites in blood samples from patients with fast- and slow-progressing ALS, identifying NATs as a key marker.
- Endocannabinoid System: NATs are part of the extended endocannabinoid system. Elevated levels in fast-progressing ALS patients are thought to be a protective but ultimately insufficient response by the body.
- PF-04457845 Validation: The compound was tested on motor neurons derived from ALS patients' iPS cells, where it limited cellular damage, and in eight-week-old ALS mice, where it extended lifespans from 129.5 days to 138 days while improving strength and preserving nerve cells.
Branch of Science: Neurology; Molecular Biology; Pharmacology.
Future Application: The compound PF-04457845 has already passed safety testing in humans, positioning it as a potential new therapeutic option for ALS. Further research will involve larger patient groups to evaluate NAT as a practical biomarker for disease severity and treatment response.
Why It Matters: Current treatments for ALS, a severe neurological disease leading to respiratory failure, only modestly slow its progression. This reverse translational approach—moving from patient blood analysis to cellular and animal models—offers a promising new target for therapies that could significantly alter the course of the disease.
The target compound, PF-04457845, has already passed safety testing in humans and may offer a new therapeutic option for ALS.
Amyotrophic lateral sclerosis (ALS) is a severe neurological disease that destroys nerve cells responsible for muscle movement. The disease typically begins with limb or bulbar weakness and progresses to respiratory failure. Current treatments only modestly slow progression, underscoring the urgent need for more effective therapies.
A team led by researchers at Nagoya University in Japan showed that blood levels of the metabolic substance N-acyl taurines (NATs) correlate with ALS progression. They also demonstrated that PF-04457845, a compound already proven to be safe in humans, slows motor decline in ALS mouse models.
ALS causes not only muscle weakness but also widespread metabolic changes, including abnormal lipid metabolism and weight loss. However, the relationship between these metabolic changes and disease progression remains unclear.
To investigate this connection, Professor Masahisa Katsuno, Assistant Professor Daisuke Ito, and colleagues at Nagoya University Graduate School of Medicine, together with researchers from Aichi Medical University and Juntendo University, analyzed metabolic changes in ALS patients.
Previous studies usually used mouse models or patient-derived induced pluripotent stem (iPS) cells, but both approaches have limitations. Mouse models reflect genetic forms of ALS, while most patients have sporadic, noninherited ALS. Patient-derived iPS cells primarily represent nerve cells, although ALS affects multiple cell types.
“We therefore began by analyzing patient blood samples to map metabolic changes and identify treatments suggested by the results,” Katsuno said.
Researchers analyzed blood samples from individuals with fast- and slow-progressing ALS, as well as healthy volunteers. Screening 867 metabolites, they identified NATs as a marker for rapidly progressive ALS. NAT is part of the extended endocannabinoid system. Further tests revealed that those with fast-progressing ALS had higher NAT levels, and individuals with the highest levels had shorter survival times.
The researchers believe that increased NAT levels reflect the body’s attempt to protect itself, although this response alone is insufficient. They suggest that boosting NAT levels with medication could help protect nerve cells.
To identify potential treatments, the team tested 29 compounds on motor neurons derived from ALS patients’ iPS cells. Results showed that PF-04457845—which blocks an enzyme that breaks down NATs—reduced degenerative changes in motor neurons, limited cellular damage, and preserved neurites.
Researchers treated 8-week-old ALS mice with PF-04457845, which extended their lifespans (138 days compared to 129.5 days without treatment), improved strength and movement, and better preserved nerve cells in the spinal cord. Healthy mice showed no effects, suggesting the benefits are specific to ALS.
Gene expression analysis showed that the drug shifts spinal cord immune cells (microglia) to a more supportive, anti-inflammatory state and directly alters genes related to nerve cell growth and function.
“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.”
The researchers plan to study larger patient groups to assess whether NAT is a practical biomarker for disease severity and treatment response. They will also continue evaluating PF-04457845 and other medications as potential therapies targeting NATs and the endocannabinoid system.
Published in journal: JCI Insight
Title: Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis
Authors: Daisuke Ito, Madoka Iida, Yohei Iguchi, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Shota Komori, Kazuki Obara, Shuto Nishisaki, Satoshi Yokoi, Teppei Shimamura, Yuto Takemoto, Masahiro Nakatochi, Tomohiro Akashi, Kunihiko Hinohara, Hyeon-Cheol Lee-Okada, Yohei Okada, Junichi Niwa, Gen Sobue, Shinji Tanaka, Ken Takashina, Takehiko Yokomizo, and Masahisa Katsuno
Source/Credit: Nagoya University
Edited by: Scientific Frontline
Reference Number: mbio082926_01
