title: Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. Although several compounds have shown promising results in preclinical studies, their translation into clinical trials has failed. This clinical failure is likely due to the inadequacy of the animal models that do not sufficiently reflect the human disease. Therefore, it is important to optimize drug target selection by identifying those that overlap in human and mouse pathology. We have recently characterized the transcriptional profiles of motor cortex samples from sporadic ALS (SALS) patients and differentiated these into two subgroups based on differentially expressed genes, which encode 70 potential therapeutic targets. To prioritize drug target selection, we investigated their degree of conservation in superoxide dismutase 1 (SOD1) G93A transgenic mice, the most widely used ALS animal model. Interspecies comparison of our human expression data with those of eight different SOD1G93Adatasets present in public repositories revealed the presence of commonly deregulated targets and related biological processes. Moreover, deregulated expression of the majority of our candidate targets occurred at the onset of the disease, offering the possibility to use them for an early and more effective diagnosis and therapy. In addition to highlighting the existence of common key drivers in human and mouse pathology, our study represents the basis for a rational preclinical drug development.
authors.affiliation: Institute of Neurological Sciences (ISN), Italian National Research Council (CNR), Catania and Mangone (CS), Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Morello
authors.affiliation: Institute of Neurological Sciences (ISN), Italian National Research Council (CNR), Catania and Mangone (CS), Italy.
authors.forename: Antonio Gianmaria
authors.initials: AG
authors.lastname: Spampinato
authors.affiliation: Institute of Neurological Sciences (ISN), Italian National Research Council (CNR), Catania and Mangone (CS), Italy.
authors.forename: Francesca Luisa
authors.initials: FL
authors.lastname: Conforti
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania, Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Agata
authors.affiliation: Institute of Neurological Sciences (ISN), Italian National Research Council (CNR), Catania and Mangone (CS), Italy. sebastiano.cavallaro@cnr.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D013482:Superoxide Dismutase
keywords: ALS; Meta-analysis; SOD1G93A mouse model; Transcriptomics