IsomiR Utility in ALS Prognostication

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are isoforms of microRNAs (miRNAs) 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. Here, we investigated the prognostic utility of plasma isomiRs in ALS. Using next-generation sequencing, we profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified several isomiRs associated with survival. These findings were independently validated in an international ALS cohort of 200 patients. Blood levels of one isomiR, let-7g-5p.t, consistently correlated with longer survival and outperformed others as a single prognostic marker. Moreover, combining let-7g-5p.t with levels of neurofilament light chain (NfL) or miR-181, substantially improved stratification of survival outcomes. These results establish isomiRs as a novel class of blood-based biomarkers in ALS and provide a step toward more refined prognostication and patient stratification strategies in clinical trials for neurodegenerative diseases.