Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood-brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition.

Keywords: advanced diagnosis; amyotrophic lateral sclerosis; bioengineering; nanotechnology; systems biology approach; therapeutic strategies.

Figure 1

An overview of the main categories of biomarkers for ALS. The figure shows fluid (black) and non-fluid biomarkers (green) investigated in association with the ALS spectrum. Each one can serve as a diagnostic, prognostic, and/or predictive tool, contributing to improve patients’ early diagnosis and advancing clinical trials, hence developing personalized treatments. Abbreviations: ALS, amyotrophic lateral sclerosis; NfL, neurofilament light chain Created in BioRender. Marcuzzo, S. (2025) https://BioRender.com/ahlgwgm.

Figure 2

An overview of the multi-omics integration approach applied to ALS. The figure illustrates how different omics layers, such as proteomics, genomics, epigenomics, transcriptomics, and metabolomics, can be simultaneously analyzed through an integrated approach. This method encompasses population-level data analysis, molecular network construction and interpretation, correlation mapping, and network-based deep learning techniques. The ultimate goal of multi-omics integration is to uncover the molecular mechanisms underlying ALS pathophysiology and identify novel therapeutic targets for innovative treatments. Furthermore, given the heterogeneous nature of ALS, the discovery of disease-specific biomarkers could enable molecular-based patient stratification, which is a critical step toward the development of personalized medicine. Created in BioRender. Marcuzzo, S. (2025) https://BioRender.com/ahlgwgm.