Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer’s Disease

Article type: Research Article

Authors: Nabirotchkin, Serguei^{a; 1; *} | Bouaziz, Jan^a | Glibert, Fabrice^a | Mandel, Jonas^a | Foucquier, Julie^a | Hajj, Rodolphe^a | Callizot, Noëlle^b | Cholet, Nathalie^a | Guedj, Mickaël^{a; 1} | Cohen, Daniel^{a; 1}

Affiliations: [a] Pharnext, Paris, France | [b] Neuro-Sys, Gardanne, France

Correspondence: [*] Correspondence to: Serguei Nabirotchkin, Pharnext, 46 Rue Saint-Lazare, 75009 Paris, France. E-mail: nabirotchkine@yahoo.fr.

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Drug combination, drug repurposing, genetics, networks, neurodegeneration, pathways, systems biology

DOI: 10.3233/JAD-220120

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1585-1603, 2022