oa Editorial (Thematic Issue: Emerging Biomarkers for Drug Development in Amyotrophic Lateral Sclerosis)

Amyotrophic Lateral Sclerosis (ALS) is a progressive, disabling neurodegenerative disorder characterized by progressive upper and lower motor neuron degeneration, leading to death from respiratory insufficiency after 3-5 years. ALS occurs either in familial (FALS; 10%) or sporadic (SALS; 90%) forms and its worldwide incidence ranges from 1.7 to 2.3 cases per 100,000 persons per year. Despite the identification of several disease-linked mutations, the etiology and pathogenesis of ALS are not well understood yet. The lack of adequate knowledge about molecular mechanisms involved in the neurodegenerative progression of ALS makes the development of effective treatments particularly difficult. Although several compounds showed promising results in preclinical studies in animal models, to date, there is no cure for ALS and the only FDA approved drug, Riluzole, has very modest efficacy on survival. A better approach to ALS therapy requires a better understanding of interactions between risk factors, pathophysiological mechanisms, biomarkers and phenotypic characteristics of patients. Thus, the aim of this special issue is to provide novel insights into both pathophysiological and pharmacological aspects of ALS. Pasquali et al. focus on the altered autophagy pathways and on the consequent formation of misfolded proteins, emphasizing the cell-to-cell protein propagation as therapeutic target in ALS. Finally, the authors discuss cell replacement therapy with focal stem cells implantation. Menon et al. discuss the role of glutamate-mediated excitotoxicity, upregulation of axonal voltage-gated persistent Na+ channel and mitochondrial dysfunction and genetic factors in ALS pathogenesis. A potential approach involving the use of antisense oligonucleotide as genetic therapy is also discussed. The main topic of the paper by Blasco et al. is excitotoxicity in ALS. The authors focus on the events implicated in this process and summarize clinical trials with drugs targeting the glutamate system, and discuss their potential role as biomarkers. The review by Lee et al. deals with therapeutic targeting of epigenetic components in ALS. The authors, in particular, point out the use of Histone Deacetylases Inhibitors (HDAC) as candidate drugs to treat disorders such as ALS. The paper by Yacila and Sari details the role of potential biomarkers identified until today and the potential role of neurotrophic peptides, drugs, stem cell therapy and immunotherapy as promising strategies for the treatment of ALS. Taken together, the reviews published in the present special issue of CMC provide the reader an extensive overview of recent findings regarding molecular mechanisms involved in ALS, emphasizing the importance of these processes as potential biomarkers and therapeutic targets and highlighting new perspectives for drug development.