The Contemporary Disease - Modifying Therapies in ALS: Clinical Evidence, Biomarkers, and Molecular Targets

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by
progressive motor neuron loss and marked biological heterogeneity. Advances in molecular
genetics and biomarker research have redefined ALS as a spectrum of molecularly distinct
subtypes, creating new opportunities for disease-modifying therapeutic development.
Aim To synthesize contemporary evidence on disease-modifying therapies in ALS, with a focus on
clinical trial outcomes, validated biomarkers, and molecular targets that inform precision
medicine approaches.
Material and Methods This narrative review integrates peer-reviewed original studies, clinical trials, and highquality
review articles published predominantly between 2017 and 2025. Literature was
selected based on relevance to ALS molecular pathophysiology, targeted therapeutic
strategies, biomarker development, and clinical trial methodology. Data were synthesized
qualitatively, emphasizing target engagement, biomarker modulation, and translational
limitations.
Results ALS pathogenesis converges on shared downstream mechanisms, including RNA
dysmetabolism, impaired proteostasis, mitochondrial dysfunction, and neuroinflammation,
despite diverse genetic drivers. Antisense oligonucleotide (ASO) therapies - particularly
targeting SOD1 - have demonstrated robust biological efficacy, including molecular target
engagement and neurofilament light chain (NfL) modulation. NfL has emerged as the most
robustly validated biomarker for prognosis, patient stratification, and pharmacodynamic
assessment, although its predictive value for long-term clinical benefit remains under
evaluation. Non–ASO disease-modifying approaches have shown variable clinical outcomes,
highlighting methodological and biological challenges. Conclusions
Disease-modifying intervention in ALS is biologically feasible but remains limited by delayed
diagnosis, disease heterogeneity, and conventional trial design constraints.