Descripción del proyecto
Fármacos activados por la luz contra la epilepsia
La epilepsia focal es una afección neurológica asociada a la emisión de señales eléctricas repentinas, excesivas e incontroladas en una parte del encéfalo, denominadas «convulsiones». Las intervenciones farmacológicas existentes no funcionan en todos los pacientes y pueden provocar efectos secundarios multiorgánicos. Para superar estas limitaciones, los científicos del proyecto financiado con fondos europeos PhotoTherEpi proponen desarrollar fármacos que se activen al administrar luz (fármacos fotoactivables). El trabajo consiste en identificar de forma sistemática varios fármacos fotoactivables «in vitro» y en un modelo murino de epilepsia para comprobar su efecto antiepiléptico. Los resultados del proyecto podrían descubrir una nueva estrategia para controlar la epilepsia focal.
Objetivo
As photo-activatable drugs (PDs) can be precisely controlled in space and time, caged and switchable photoactivatable drugs (CPDs, SPDs) are rapidly emerging as potential therapeutics for varied forms of cancer, vision loss, diabetes, or pain disorders. Despite their potential, PDs have not been exploited for epilepsy, a common, often debilitating neurological disorder. As 30% of epilepsies are medically intractable, and antiepileptic drugs often cause multi-organ side effects, PDs could break new therapeutic ground. PDs can be applied on demand, and locally activated/inactivated in single or multiple epileptic brain areas in a targeted fashion. This minimizes systemic side effects, and allows the application of potent drugs from other fields yet unthinkable in routine epileptology (e.g. general anesthetics). Importantly, being small molecules, different PDs can be combined or easily exchanged, and do not require protein expression. Using current and new PDs, we aim to control epileptic networks in vivo in a realistic epilepsy mouse model, and resected human brain tissue from patients with intractable epilepsy. Aim 1 will quantify antiepileptic potency of a range of PDs in human tissue using field potential and patch-clamp recordings, and cellular scale 2-photon imaging. In aim 2, PDs will be evaluated in vivo using wireless video-EEG, imaging and light-fiber-targeted drug photoactivation in chronically epileptic mice. Further, by use of caged immunomodulators, we will explore disease-modifying capacity of targeted PD photoactivation in epileptogenesis and chronic epilepsy. PhotoTherEpi will establish targeted photopharmacology as a versatile, and powerful new approach to control focal epilepsy, which could jumpstart a new branch of translational epilepsy research. The approach could obviate the need for resective surgery in many cases, and be used in multi-focal epilepsy. Importantly, it may be clinically tested in the foreseeable future.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
53127 Bonn
Alemania