title: Identifying new antiepileptic drugs through genomics-based drug repurposing.
abstract: Currently available antiepileptic drugs (AEDs) fail to control seizures in 30% of patients. Genomics-based drug repurposing (GBR) offers the potential of savings in the time and cost of developing new AEDs. In the current study, we used published data and software to identify the transcriptomic signature of chornic temporal lobe epilepsy and the drugs that reverse it. After filtering out compounds based on exclusion criteria, such as toxicity, 36 drugs were retained. 11 of the 36 drugs identified (>30%) have published evidence of the antiepileptic efficacy (for example, curcumin) or antiepileptogenic affect (for example, atorvastatin) in recognised rodent models or patients. By objectively annotating all ∼20,000 compounds in the LINCS database as either having published evidence of antiepileptic efficacy or lacking such evidence, we demonstrated that our set of repurposable drugs is ∼6-fold more enriched with drugs having published evidence of antiepileptic efficacy in animal models than expected by chance (P-value <0.006). Further, we showed that another of our GBR-identified drugs, the commonly-used well-tolerated antihyperglycemic sitagliptin, produces a dose-dependent reduction in seizures in a mouse model of pharmacoresistant epilepsy. In conclusion, GBR successfully identifies compounds with antiepileptic efficacy in animal models and, hence, it is an appealing methodology for the discovery of potential AEDs.
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
authors.forename: Nasir
authors.initials: N
authors.lastname: Mirza
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
authors.forename: Greame J
authors.initials: GJ
authors.lastname: Sills
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Marson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D058492:Drug Repositioning / Q000379:methods*; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D051379:Mice; D012640:Seizures / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012984:Software; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics
chemical_list: D000927:Anticonvulsants