TrilliAED

Anti-epileptic drugs (AED) are prescribed in 70 Ms of patients worldwide, yet without curing epilepsy. Adverse-drugs events are frequent and diverse, often impairing patients’ quality of life. Children are at higher risk of developing epilepsy and approx. 25% will not respond to available AED. Pharmacoresistance to AED (~30 molecules) is a major burden to patients and society. The brain suffers during the time needed for the physician to empirically find a treatment and refractory epilepsy in young children is associated with severe sequelae. Drug toxicity can also have disastrous consequences Numerous hypotheses explaining resistance to AEDs have been addressed and involve genetic and epigenetic host factors, disease severity, transporters and targets hypothesis etc. Yet success rate of AEDs has not improved over the last 20 years. TrilliAED will consider the trillions of bacteria from the gut microbiome as potential effectors of AED response in children. The TrilliAED project’s objectives are to i) demonstrate the link between the human microbiome and response to AED in children, ii) define why and how specific microbiomes may sustain or boost AED efficacy, lowering adverse events, both in vitro and in vivo, iii) stratify patients to suggest appropriate therapeutic options early in the disease development by implementing an innovative “microbiomic” approach, and iv) ameliorate effectiveness of these otherwise valuable and affordable molecules. To reach these goals, gut microbiome variations depending on response to AED will be explored in a pediatric cohort. Then, bacteria of interest will be scrutinized for their drug metabolism capacity. Toxicity of drug degradation secundary products will be assessed in vitro. Finally, findings will be recapitulated in animal models of seizures and bacterial add-on therapies will be proposed. Since uncontrolled seizures occurrences strongly affect social interactions but also education in these developing brains, being able to provide an efficient treatment option to these patients as early as possible, to modulate their microbiome to improve their response to available treatments or to decrease debilitating adverse events is a crucial societal, scientific and medical need.