A Systems Biology Approach for Personalized Medicine in Refractory Epilepsy

Abstract

Epilepsy refers to a common chronic neurological disorder that affects all age groups. Unfortunately, antiepileptic drugs are ineffective in about one-third of patients. The complex interindividual variability influences the response to drug treatment rendering the therapeutic failure one of the most relevant problems in clinical practice also for increased hospitalizations and healthcare costs. Recent advances in the genetics and neurobiology of epilepsies are laying the groundwork for a new personalized medicine, focused on the reversal or avoidance of the pathophysiological effects of specific gene mutations. This could lead to a significant improvement in the efficacy and safety of treatments for epilepsy, targeting the biological mechanisms responsible for epilepsy in each individual. In this review article, we focus on the mechanism of the epilepsy pharmacoresistance and highlight the use of a systems biology approach for personalized medicine in refractory epilepsy.

Keywords: GABAA receptor; drug transporters; epilepsy; functional genomics; pharmacogenomics; pharmacoresistance.

Figure 1

Schematic representation of the main pharmacokinetic (a) and pharmacodynamic processes (b) of antiepileptic drugs involved in refractory epilepsy. Mutations in genes encoding molecular targets could cause structural and/or functional alterations responsible for the lack of response to pharmacological treatment.

Figure 2

Illustrative representation of pharmacogenomics temporal evolution: from monogenic to complex genetic research analysis. (A) Genetic screening tests reveal variants correlated to the etiology of drug resistance in epilepsy. (B) Application of genetic technologies (NGS and CGH) integrated together with computational strategies allows the identification of casual disease networks and stratification of patients towards the personalized medicine.