IsomiR utility in amyotrophic lateral sclerosis prognostication

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored. Methods: Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches. Findings: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181. Conclusions: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with the potential to refine prognostication in clinical trials for neurodegenerative diseases. Funding: This study was funded by Target ALS the Israel Science Foundation (3497/21, 424/22) and the CReATe Consortium. All additional funding can be found under the Acknowledgments.