Systematic Approach for Drug Repositioning of Anti-Epileptic Drugs

Abstract

Epilepsy is a central neurological disorder affecting individuals of all ages and causing unpredictable seizures. In spite of the improved efficacy of new antiepileptic drugs and novel therapy, there are still approximately 20%~30% of patients, who have either intractable or uncontrolled seizures. The epilepsy drug-target network (EDT) is constructed and successfully demonstrates the characteristics and efficacy of popularly used AEDs through the identification of causative genes for 60 epilepsy patients. We discovered that the causative genes of most intractable patients were not the targets of existing AEDs, as well as being very far from the etiological mechanisms of existing AEDs in the functional networks. We show that the existence of new drugs that target the causative genes of intractable epilepsy patients, which will be potential candidates for refractory epilepsy patients. Our systematic approach demonstrates a new possibility for drug repositioning through the combination of the drug-target and functional networks.

Keywords: NGS; drug repositioning; drug-target network; epilepsy; precise medicine.

Figure 1

Data Integration Schema: Data source for drug-target information, epilepsy causative genes, and protein-protein interaction and their statistics.

Figure 2

Clinically used anti-epileptic drugs (AED), Targets, and epilepsy-associated genes. (a)Highly targeted gene by AEDs, the x-axis represents the target genes of 13 clinically used AEDs, the y-axis represents the number of drugs targeting the genes. CGTG represents that it is an epilepsy-causative gene as well as a target gene of AEDs, and TG represents that it is only a target gene of AEDs (b) Target distribution of 13 clinically used AEDs, blue bar represents the number of target genes, red bar represents the number of epilepsy-associated target genes.

Figure 3

The EDT-drug network; AED-target genes-epilepsy associated gene network, red nodes represent the 13 clinically used AEDs, yellow nodes represent targets of AEDs as well as epilepsy-associated genes, skyblue nodes represent the targets of AEDs, and green nodes represent the epilepsy-associated genes not targeted by current AEDs.

Figure 4

The top ranked drugs targeting epilepsy causative genes and the summary statistics of known drugs and their targets. (a) The x-axis represents the number of epilepsy causative genes targeted by listed drugs. Note that Ethanol is a top ranked drug targeting 40 epilepsy causative genes. L-Glutamic acid and zonisamide are also top-ranked drugs; each of them targets 39 and 30 genes, respectively. (b) The x-axis represents the number of drugs targeting the epilepsy causative genes, and the y-axis represents the number of genes. Note that most of epilepsy-causative genes (e.g., 433 genes) are targeted by less than five drugs. (c) The x-axis represents the number of epilepsy-causative genes based on GENECARD and the y-axis represents the number of drugs. For example, most of drugs (2209 drugs) target less than five epilepsy-causative genes.