Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer’s Disease
| Autor: | Serguei, Nabirotchkin, Jan, Bouaziz, Fabrice, Glibert, Jonas, Mandel, Julie, Foucquier, Rodolphe, Hajj, Noëlle, Callizot, Nathalie, Cholet, Mickaël, Guedj, Daniel, Cohen |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Alzheimer's Disease. 88:1585-1603 |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | Background: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. Objective: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. Methods: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. Results: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. Conclusion: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer’s disease. |
| Databáze: | OpenAIRE |
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