Skeletal muscle biomarkers of amyotrophic lateral sclerosis: a large-scale, multi-cohort proteomic study
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Background
Biomarkers with clear contexts-of-use are important tools for 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. SOMAmer (Slow Off-rate Modified Aptamer)-based relatively quantitative measurement of ∼7,000 proteins was performed in plasma and 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, while ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (e.g. PDLIM3, TNNT2, MYL11) or decrease (e.g. ANTXR2, ART3, 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. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.
Conclusion
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.
(Key messages)
What is already known on this topic
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There are currently few monitoring and disease progression biomarkers in ALS; and there is no published work from large-scale, multi-cohort proteomic studies that utilized longitudinal plasma and CSF samples to help fill this gap.
What this study adds
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Using Slow Off-rate Modified Aptamer (SOMAmer)-based methods, we have identified an array of novel biomarkers of disease state (i.e. differentially regulated in ALS vs. controls) and ALS disease progression. These included, among others, PDLIM3, MYL11, ANTXR2, ART3, and MSTN.
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Skeletal muscle is the likely source of many of these newly discovered biomarkers.
How this study might affect research, practice or policy
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These newly identified monitoring and disease progression biomarkers may be used to evaluate pharmacodynamic response in future clinical trials, thereby aiding ALS therapy development efforts.
