altering neuronal coding properties and excitability. Working closely with Christophe Mulle, we demonstrated that ectopic KARs containing the GluK2 subunit play a key role in triggering recurrent seizures. This establishes GluK2 as a promising therapeutic target for drug-resistant epilepsy.
Building on this foundation, we initiated a strategic maturation phase in partnership with INSERM Transfert, SATT Aquitaine, Regenxbio, and Kurma Partners to develop a proof-of-concept gene therapy strategy targeting GluK2 in the hippocampus. This collaborative effort resulted in the establishment of Corlieve Therapeutics, co-founded with Christophe Mulle and bringing together :
- academic partners – INSERM via INSERM Transfert, and CNRS via SATT Aquitaine,
- alongside industrial partners – Kurma Partners, Regenxbio, Eurazeo, Pureos, and Bpifrance)
See Valérie Crépel, Prix Innovation 2022 and Corlieve Therapeutics rachetée par la biotech uniQure : un transfert réussi.
Following Corlieve’s acquisition by uniQure, the development of the AMT-260 drug candidate was accelerated and has now advanced to a Phase I/IIa clinical trial – see more
Selected references at the bottom of the page
Scientific Interests
We investigate neuronal computation and plasticity in normal and pathological conditions. Our studies are conducted at multiscale levels i.e. from the individual spine to the microcircuit.
Disease conditions: Temporal Lobe Epilepsy and Traumatic Brain Injury.
Key words: hippocampus, cerebellum, synapse, intrinsic property, plasticity, synaptopathy, calcium
Technical skills: (i) in vitro and in vivo electrophysiological recordings; (ii) calcium imaging; (iii) morphometric analysis; (iv) optogenetic; (v) spatial navigation in virtual reality environments.
Kainate receptors in the physiopathology of temporal lobe epilepsy
Temporal Lobe Epilepsy (TLE) is the most common form of partial epilepsy in adults is often refractory to pharmacological medication. Moreover, patients with TLE also often suffer from comorbid disorders including cognitive impairments. Therefore, it is crucial to better understand the physiopathology of TLE in order to propose new anti-epileptic strategies and shed light on putative alterations of neuronal computation.
We show that recurrent mossy fibers synapses operate via kainate receptors not present in naïve conditions (Epsztein et al. 2005). These synapses profoundly affect synaptic transmission by generating synaptic events with slow kinetics. Because of this feature, we show that KAR-operated synapses impose an aberrant synaptic temporal integration, a wrong tempo of firing and trigger a long-lasting intrinsic plasticity in epileptic dentate granule cells (Epsztein, Sola et al. 2010; Artinian et al. 2011; Artinian et al 2015). We propose that these changes of neuronal computation may contribute to the impairment of dentate gyrus functions such as gate function and pattern separation in TLE.
In collaboration with C. Mulle (IINS, Bordeaux), we recently demonstrate that GluK2/GluK5 kainate receptors ectopically expressed in dentate granule cells play a major role in recurrent seizures in TLE (Peret, Christie et al. 2014;Crepel and Mulle 2014). This should revitalize the development of new pharmacological agents and strategies directly targeting these KARs as novel antiepileptic drugs: INSERM Transfert filed patent: WO/2015/036618.
Collaborators
INMED
Dr. C Rivera
Dr. R. Khazipov
Dr. R. Cossart
Dr. A. Torcini
Dr. J. Epsztein
Dr. PP Lenck-Santini
Dr. I. Bureau
Dr. Represa
EXTERNAL
Dr. C. Mulle (Institut des Neurosciences, Bordeaux)
Pr. F. Bartolomei (Hopital Timone, Marseille)
Pr. D. Scavarda (Hopital Timone, Marseille)
Dr. Jean-François Perrier (Copenhagen, Danemark)
Dr. M. Simonneau (Centre de Psychiatrie & Neurosciences, Paris)
Former members
– Jérôme Epsztein (CR1, INSERM)
– Thomas Scalfati (Master Student)
– Saara Valpurla (Master Student, Erasmus)
– Julien Artinian (Post-doc.)
– Geoffrey Marti (Master Student)
– Louisa Christie (Post-Doc.)
– David Ouedraogo (PhD student)
– Yanina Mircheva (Master Student)
– Karen Arnaud (Master Student)
Funding
2013 – 2017 : ANR « Blanc » (TRAUMEP, C. RIVERA & V. CREPEL)
2013-2014: LFCE (A. PERET, V. CREPEL)
2011 : région PACA : Appel à Projets Ouverts (projet APO, V. CREPEL)
2011-2012: LFCE (J. ARTINIAN, V. CREPEL)
2010 – 2014: ANR « Blanc » (KAREP, C. MULLE & V. CREPEL)
2010 FRC / Rotary (A. REPRESA & V. CREPEL)
2009 – 2012: ANR « Blanc » (Epileptic Code, V. CREPEL)
2006 – 2009: ANR MNP (CDDRat, A. REPRESA & V. CREPEL)
Join our team !
Our team has open positions for master students, PhD students and post-docs. Please send your application by email to Valérie Crépel
