Human Neurogenetics
Chef d'équipe
L. VILLARD
L. VILLARD
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 different projects.
We developed original projects for developmental and epileptic encephalopathies while constituting one of the largest European cohorts of patients (1300 patients as of june 2020). We have identified several "candidate" genes for DEE using comparative genomic hybridization (CGH) or exome sequencing. We redefined the clinical and electroclinical characteristics of DEE caused by mutations in several genes and identified mutations in several new epilepsy genes. In parallel, we have developed models for electrophysiology and pre-clinical research (a new KI mice and human neurons derived from induced pluripotent stem cells).
In parallel, Laurent 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 next generation sequencing technologies: the EPIGENE network.
Our research in the field of Rett syndrome has started twenty years ago. 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-based industrial). We also validated the use of adeno-associated viruses (AAV9) 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 Rett syndrome European database.
For the next few years, our keywords will be high throughput genotyping and pre-clinical research. For the project on DEE, 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.
The overall strategy of the team is to build perfectly phenotyped and genotyped 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. We hope that our future work will provide other examples in order to provide the much needed treatments to affected individuals and their families.
Our work is supported by grants from ANR, H2020, Fondation JED, Région PACA, Association Française du Syndrome de Rett, AFM Téléthon, Rettsyndrome.org, Fondation Maladies Rares, Promex Stiftung Für Die Forschung, Inserm and Aix Marseille Université.
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Téléphone: 04 91 32 49 03
PH
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POST-DOC
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IE
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PUPH
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PH
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CR1
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IR
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DOCTORANT(E)
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DR2
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TCH
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CRCN
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DR2 Inserm (PhD - HDR)
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Téléphone: 04 91 32 49 03