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. 2025 Sep 29.
doi: 10.1002/ana.78046. Online ahead of print.

Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study

Oleksandr Dergai  1 , Joanne Wuu  2 , Magdalena Koziczak-Holbro  1 , Andrea Malaspina  3 , Volkan Granit  2 , Jessica P Hernandez  2 , Anne Cooley  2 , Ruchika Sachdev  4 , Lili Yu  5 , Michael Bidinosti  1 , Ludivine Flotte  1 , Mark Nash  1 , Lori L Jennings  6 , James D Berry  7 , Lucie I Bruijn  8 , Sophie Brachat  1 , Michael Benatar  2
Affiliations

Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study

Oleksandr Dergai et al. Ann Neurol. .

Abstract

Objective: Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.

Methods: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off-rate modified aptamer (SOMAmer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.

Results: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, whereas ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.

Interpretation: 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 disease. ANN NEUROL 2025.

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References

    1. Bensimon G, Lacomblez L, Meninger V, the ALS/Riluzole study group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994;330:585–591.
    1. The Writing Group on behalf of the Edaravone (MCI‐186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double‐blind, placebo‐controlled trial. Lancet Neurol 2017;16:505–512.
    1. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide Tofersen for SOD1 ALS. N Engl J Med 2022;387:1099–1110.
    1. Benatar M, Boylan K, Jeromin A, et al. ALS biomarkers for therapy development: state of the field and future directions. Muscle Nerve 2016;53:169–182.
    1. FDA‐NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource, Available at: https://www.ncbi.nlm.nih.gov/books/NBK326791/. Accessed April 2023, 2016.

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