The permanent staff making up this team has complementary skills in the field of clinical genetics, molecular genetics, neurophysiology and paediatric neurology. Several physicians are team members and actively participate in the projects in the field of intellectual disability and epilepsy. We have established and maintain strong links with the local, national and international hospital environments.
We developed original projects for early onset epileptic encephalopathies while constituting the largest European cohort of patients (560 patients as of July 2017). We have identified several "candidate" genes for EOEE using comparative genomic hybridization (CGH) or exome sequencing. We redefined the clinical and electroclinical characteristics of EOEE caused by mutations in several genes and identified mutations in two new epilepsy genes. In parallel, we have developed models for electrophysiology and pre-clinical research (new KI mice and human neurons derived from induced pluripotent stem cells (iPS) ). Recently, we have discovered a new mechanism explaining the severe epilepsies caused by KCNQ2 gene mutations.
In parallel, a researcher of the team (L. Villard) is responsible for the molecular diagnosis of genetic epilepsies in the Department of Medical Genetics (La Timone Children's Hospital). In 2015, this activity led to the creation of a national network under the umbrella of the ANPGM (association of professionals in charge of molecular genetics testing), using high-throughput sequencing technologies.
For our activities in the field of Rett syndrome, we discovered and documented bioaminergic abnormalities in several brain structures involved in autonomic function and the development of motor strategies in an animal model of the disease. We have demonstrated the interest of desipramine to treat autonomic dysfunction in an animal model of RTT and obtained an orphan drug designation from the European Medicine Agency (EMA). We also discovered an axonal transport defect in the animal model of RTT (patented). The results with desipramine and on axonal transport have led to the establishment of two clinical trials for Rett syndrome patients (one of which has been licenced to a US industrial). We also validated the use of adeno-associated viruses (AAV) for gene therapy in Rett syndrome using a mouse model of RTT (with the support of the French muscular dystrophy associated, AFM). Finally, we have structured a European network of professionals in collaboration with the European Federation of RTT associations (RSE) and developed a European database now containing 2,000 files.
For the next few years, our keywords will be high throughput genotyping and pre-clinical research. For the project on EOEE, we now have unique models handy (patient neurons and knock-in mice), which will allow us to better comprehend the neuronal abnormalities induced by mutations in the most frequent disease-causing genes. For Rett syndrome, we place great hope in the partnerships that have been forged with physicists and with a company specializing in the development of molecules crossing the blood brain barrier to enable us to significantly improve the penetration of virus particles or candidates molecules in the brain of mouse models. Furthermore, we will invest into alternative (out of the mainstream) projects to study neuroinflammation, the glial secretome and lipidomics, allowing us to be less exposed to the fierce international competition that exists in the field of Rett syndrome.
The overall strategy of the team is to build perfectly phenotyped and genotyped large cohorts as a first line, in order to better understand the clinical and genetic landscape of the studied diseases. We will implement research projects to study pathophysiology using several models (mostly animal models). We already master the cellular studies and the phenotyping of rodents, and we will develop the study of zebrafish as a new and promising model. Equipped with original findings on pathophysiology, we hope to offer new treatments after in vivo testing of our original models, in collaboration with industrial partners when appropriate.
The recent history of our team shows that we successfully travelled twice the virtuous circle going from basic research to clinical trials in patients, and we hope that our future work will provide other examples during the next term.