Signature-Based Computational Drug Repurposing for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. There are currently limited approved drugs for the disorder, and for this reason the strategy of repositioning already approved therapeutics could exhibit a successful outcome. Herein, we used CMAP and L1000CDS ² databases which include gene expression profiles datasets (genomic signatures) to identify potent compounds and classes of compounds which reverse disease's signature which could in turn reverse its phenotype. ALS signature was obtained by comparing gene expression of muscle biopsy specimens between diseased and healthy individuals. Statistical analysis was conducted to explore differentially transcripts in patients' samples. Then, the list of upregulated and downregulated genes was used to query both databases in order to determine molecules which downregulate the genes which are upregulated by ALS and vice versa. These compounds, based on their chemical structure along with known treatments, were clustered to reveal drugs with novel and potentially more effective mode of action with most of them predicted to affect pathways heavily involved in ALS. This evidence suggests that these compounds are strong candidates for moving to the next phase of the drug repurposing pipeline which is in vitro and in vivo experimental evaluation.
(© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)