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Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies
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DOI：10.1186/s13287-025-04781-w.png)
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Abstract
En 中文
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective loss of motor neurons (MNs), leading to progressive muscle weakness, atrophy, and ultimately paralysis. This review provides a comprehensive overview of the molecular mechanisms underlying ALS pathogenesis, the genetic mutations associated with both familial and sporadic forms of the disease, and the latest therapeutic strategies aimed at mitigating disease progression. mutations in genes such as C9orf72, SOD1, TARDBP, and FUS have been implicated in ALS, with an intricate interplay of protein misfolding, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation contributing to motor neuron degeneration. While current FDA-approved treatments such as Riluzole and Edaravone offer only modest benefits and do not significantly halt disease progression. Emerging therapies, including gene therapies (e.g., antisense oligonucleotides (ASOs) and CRISPR/Cas9, stem cell-based approaches, and neurotrophic factor supplementation, are demonstrating promising results in preclinical and early-phase clinical trials. novel approaches aim to target, modulate, and promote regeneration, renewed hope for future ALS treatments. However, several challenges remain, including effective delivery methods, safety concerns, and the inherent complexity of ALS pathology, ongoing research continues to explore these innovative interventions with the goal of improving clinical outcomes for patients. This review highlights the importance of personalized therapeutic approaches and underscores the necessity of continued innovation in ALS research, with the ultimate goal of developing disease-modifying therapies and, potentially, a cure for this fatal condition. Amyotrophic Lateral Sclerosis, Neurodegenerative Diseases, C9orf72 Mutation, SOD1 Mutation, Riluzole This comprehensive review article presents an in-depth analysis of the molecular pathogenesis of Amyotrophic Lateral Sclerosis (ALS), emphasizing the complex interplay of genetic mutations, protein misfolding, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation that collectively drive motor neuron degeneration. By systematically categorizing ALS subtypes based on genetic, clinical, and molecular characteristics, the article elucidates the diverse mechanisms underlying both familial and sporadic forms of the disease. Notably, it highlights key genetic mutations such as those in C9orf72, SOD1, TARDBP, and FUS and details how these contribute to disease pathology through distinct molecular pathways. The review integrates recent advances in understanding ALS heterogeneity and the impact of gene-environment interactions and epigenetic factors, underscoring the necessity for personalized therapeutic approaches. A novel aspect of this review is its comprehensive coverage of cutting-edge therapeutic strategies targeting ALS at the molecular level, including gene therapies like antisense oligonucleotides (ASOs), RNA interference, and CRISPR/Cas9 gene editing, alongside stem cell-based treatments and antibody-mediated interventions. The article critically evaluates the current state of FDA-approved drugs, such as Riluzole and Edaravone, noting their limited efficacy, while bringing to light promising preclinical and clinical trial data on novel treatments aimed at halting or reversing disease progression. Furthermore, it discusses the challenges inherent in delivering therapies across the blood-brain barrier, safety concerns, and the need for robust clinical trial designs. By integrating molecular insights with therapeutic innovations and clinical perspectives, this review advances the field by providing a valuable roadmap for future research focused on developing effective, disease-modifying treatments for ALS.
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