Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis

• Published in: Neurotherapeutics Vol. 18; no. 3; pp. 1678 - 1691
• Main Authors: Fiscon, Giulia, Conte, Federica, Amadio, Susanna, Volonté, Cinzia, Paci, Paola
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2021; Springer Nature B.V
• Subjects: Algorithms; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - diagnosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Angiotensin; Biomedical and Life Sciences; Biomedicine; Catecholamines; Central Nervous System Stimulants - pharmacology; Central Nervous System Stimulants - therapeutic use; Clomipramine; Disease; Drug Repositioning - methods; Gene Regulatory Networks - drug effects; Gene Regulatory Networks - genetics; Gene set enrichment analysis; Histamine; Humans; Isoenzymes; Mianserin; Modafinil; Neurobiology; Neurological diseases; Neurology; Neuromodulation; Neurosciences; Neurosurgery; Original; Original Article; Pathogenesis; Prostaglandin endoperoxide synthase; Protein Interaction Domains and Motifs - drug effects; Protein Interaction Domains and Motifs - genetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Serotonin transporter; Therapeutic targets; γ-Aminobutyric acid; Drug repositioning; Amyotrophic lateral sclerosis; Modafinil; Network Medicine; Histaminergic drugs
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-021-01064-z

The continuous adherence to the conventional “one target, one drug” paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.