CANDLE

Epilepsy is a serious neurological disease affecting about 65 million people worldwide. In 2010, the WHO’s Global Burden of Disease study ranked epilepsy as the second most burdensome neurological disorder in terms of disability-adjusted life years. This project aims to solve the challenging clinical problem of defining the optimal drug therapy in the patient-specific context of epilepsy.

Indeed, for 70% of epileptic patients, long-term anti-seizure drugs (ASDs) remain the mainstay of treatment.

Despite the approval of a large number of antiepileptic drugs over the past 25 years, there has been no significant improvement in treatment efficacy, and one-third of patients suffer from intractable epilepsy. This has led to the search for alternative drug discovery solutions, such as drug screening which refers to the process of evaluating new potential medications to determine their effectiveness in preventing or controlling seizures. Combined with in vitro or in vivo models of epilepsy, drug screening technologies have proved useful to assess the safety, efficacy,

and pharmacokinetics (how the drug is absorbed and metabolized) of antiepileptic drugs. However, their aim is not to determine the optimal therapeutic approach based on already existing approved ASDs.

The primary objective of this ” CANDLE ” project is to propose a radically new approach to address this problem. The most innovative aspect is the development of neurobiologically and neurophysiologically plausible computational (syn. biomathematical) models in order to identify the best mono- or polytherapy using ASDs which are currently available in clinical practice. This novel approach is high-risk due to its high level of innovation (no other existing study, to the best of our knowledge). It is also high-gain as it can lead to a groundbreaking clinical tool (i.e. an aid to optimize drug therapy) that is much needed in the care of patients with epilepsy.

The research strategy is organized around three interdisciplinary work packages to establish a first proof of concept of the proposed approach and assess the expected progress beyond classical drug screening methods. In WP1, we will develop computational modeling of ASD dynamics at the cellular level, neuronal population level and at whole brain level (digital twin). The objective of WP2 is to experimentally validate the proposed computational models using experimental in vivo models of epilepsy. Then, WP3 aims to validate the proposed models in patients undergoing ASD therapy.

The consortium includes partners with complementary and recognized expertise in clinical epileptology, neurobiology, and computational neurosciences. This is a strong asset that guarantees 1) an easy access to clinical data (clinical reports and observations) in a large cohort of patients with epilepsy and high quality experimental data recorded in in vivo models.

If successful, the CANDLE project will be a technological breakthrough with a major clinical impact.