WP coordinator(s): E. Hirch ; B. Zalc ; JC Corvol (Node 2)
WPs collaborators: P. Hantraye & L. Hertz-Pannier (Node 1) ; N. Cartier (Node 4) ; C. Chiron (U663); P. Gressens (U676)
The aim of WP4 is to fill the gap between fundamental discoveries in terms of new targets or putative pharmacological hits in the field of neurological diseases and their therapeutic applications, in adults and children. Our major objectives will be to overcome the challenges faced by academic research when translating results from bench to bedside, thus accelerating the process.
A battery of tests, in vitro in culture dishes and in vivo in a large panel of animal models (both toxin-related and genetic) and finally in humans will be provided in our center for clinical investigation which will allow academic or industrial researchers to begin by revalidating their target and reach up to phase I/II trials in patients. The CR-ICM possess a large panel of both in vitro and in vivo models/tools enabling the identification of physiologic pathways and therapeutic targets involved in the major neurological diseases in adults and the screening of potential therapeutic candidates.
| Pathology | In vitro | In vivo |
|---|---|---|
| Multiple Sclerosis |
Myelinating co-cultures, Primary oligodendroglial cultures Cell lines |
Chemically-induced (lysolecithin; cuprizone) demyelination models (rodent) MOG-EAE (rodent) Genetic model of chemically-induced demyelination (Xenopus) |
| Parkinson | Primary cell cultures of dopaminergic, noradrenergic, GABAergic brain regions, Stem cells and iPS (rodent, human) |
Chemically-induced (MPTP, rotenone, annonacine) DA cell death (rodent, primate) Genetically-induced (DA cell death modelsαGenetically-induced ( (rodent) |
| Alzheimer | Neurons in microfluidic chambers | Genetically-induced (APP ; presenilin (rodent) |
| Epilepsy | Tissue slices (rodent, human) | Gaers rat Genetically-induced mutants (Ion channel) (mouse) |
| Amyotrophic lateral sclerosis |
Motoneuron-microglial co-cultures (rodent) |
Genetically-induced mutants (rodent, zebra fish) |
| Brain tumor | Glioblastoma-derived cell lines (human) | Transplantation in immunotolerant mouse |
| Orphan diseases | Stem cells and iPS (rodent, human) | Genetically-induced mutants (SCA7 mouse) |
A similar translational approach will be proposed for two major diseases of developing brain (cerebral palsy and epilepsy), a research field still largely unexplored. Nonetheless, preclinical testing of paediatric drugs has become a compulsory step in accordance with the European Pediatric Regulation enforced in 2007 on the “need for non-clinical testing in juvenile animals of human pharmaceuticals for pediatric indications”.
THE NeurATRIS Infrastructure will combine rodent and non-human primate immature models along with human pediatric tissues, and in vitro/in vivo/in silico models, in order (1) to image perinatal neuroprotection using MRI, (2) to study Blood-Brain-Barrier (BBB) during brain development and and its permeability to various drugs, (3) to simulate and modelling clinical trials at pediatric ages. Due to the specificities of the immature brain models, and the many ethical and practical specificities of clinical trials in neonates and children, this part of the WP will be performed in U676 (Paris 7) and U663 (Paris 5).
The objective is to implement and develop new methods to screen compounds with therapeutical activity in different neurological diseases, to validate proposed targets and to revalidate them using alternative models.