This project will test the efficacy, safety and mechanism of action of Cannabidiol (CBD) and Cannabidivarin (CBDV) for fragile X syndrome (FXS), a rare genetic disease (ORPHA908) leading to intellectual disability and autism, for which no effective treatment exists. CBD and CBDV are non-psychoactive components of Cannabis that have recently garnered a lot of scientific and industry interest. In 2019, CBD has been approved by EMA for two epilepsy syndromes associated with autism, while CBDV is currently under clinical trial to assess its efficacy in people with autism. Furthermore, preliminary clinical data show that CBD improves social anxiety in FXS patients, suggesting that CBD may be effective in managing the behavioral symptoms of FXS. However, these clinical studies have intrinsic limitations that make the interpretation of the findings challenging. Furthermore, the mechanisms underlying the beneficial effects of CBD and CBDV in FXS are unknown. This project will use a multidisciplinary approach to translate these potential treatments from bench to bedside and to guide future clinical trials. We will: 1. Test the efficacy and safety of CBD and CBDV in an animal model that displays the key features of FXS. 2. Unravel the mechanisms underlying the effects of CBD and CBDV in FXS. The available resources, preliminary data and experience of the researchers involved in this project guarantee project feasibility. Scheduled meetings with company stakeholders and patient associations will bridge the gap from basic research to the drug market, to patient families and society.

Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes located on this chromosome and which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In this project, we focus on the CBS gene, which encodes an enzyme, Cystathionine Beta Synthase, suspected to be involved in the dysfunction of mitochondria in DS. Indeed, this enzyme is involved in the production of H2S in the brain. At low concentration, H2S promotes mitochondrial activity whereas at high concentration, it inhibits an important part of the mitochondrial respiratory chain, an important cellular actor important for the production of energy. Studies have shown that the reduction of CBS activity could rescue mitochondrial defects in DS fibroblasts. Unfortunately, so far, the attempts to identify pharmacological inhibitors of CBS have only led to the identification of molecules that are not efficient enough. The aim of our project is to assess the therapeutic potential of three new CBS inhibitors, that we have recently identified. We plan to test their activity on cellular models and on phenotypes that are relevant to the pathophysiology of Down syndrome, e.g. the mitochondrial defects observed in skin cells (fibroblasts) and neural progenitor cells (NPC) derived from induced pluripotent cells (iPSC) from DS patients. Then, as these three molecules have never been tested in the animal, we propose to generate preliminary studies in mouse to see whether these molecules are not too toxic, whether they can reach the brain and how efficient they are to inhibit CBS. Our final aim is to generate relevant data to decide whether one or several of these compounds could be tested in mouse or rat models for DS, and could be later a good candidate drug to reduce the cognitive difficulties of DS patients.

It is estimated that worldwide 2-4% of children are affected by  a neurodevelopmental disorder, and more specifically 1-2 % suffer from autism spectrum disorder (ASD) . The advent of fast and inexpensive genome sequencing technologies has enabled the identification of new genes involved in ASD and thereby also  greatly  helped the correct diagnosis of patients. One relatively novel disorder is termed Okur Chung neurodevelopmental disorder, in short OCNDS which, like other ASD syndromes, is characterized by motor and cognitive impairment, hypotonia, gastrointestinal issues, epilepsy and more. We want to understand if the common problems in the gut are caused by alteration in the microbial composition and whether these changes may also  affect the brain, leading to inflammation and ultimately to behavioral symptoms. This field of research is very exciting since the gastrointestinal microflora can be easily  changed through medication or even diet.

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by genetic defects within a locus on chromosome 15 (15q11-q13), in which the loss of expression of paternally inherited genes cause severe symptoms; for example neurodevelopmental delays, hyperphagia and obesity, as well as various disturbances in the rhythms of sleep and wakefulness. This parent-of-origin genetic mechanism, namely genomic imprinting, emerged during evolution of placental mammals and accumulated pivotal functions in organismal homeostasis, metabolism and sleep-wake behaviours. All these functions follow 24-h cycles and rely on the molecular organization of networks of cellular oscillators, the circadian clock system. To date the dynamics and the rate-limiting factors for gene expression within cells remain unknown; recently we have identified an appealing mechanism, a nuclear pore functions, which promises to reveal an understanding of how abundance of mRNA across different cellular compartments depends on the circadian clock and sense the metabolic state of the cell. The results of our investigation may lead to a better comprehension of why PWS patients, which are lean in infancy due to feeding difficulties, later develop obesity and sleep disturbances. By studying the role of a PWS human gene in mice we will be able to test whether this is a suitable therapy for individuals with PWS. Last but not least, we developed an epigenetic editing technology as novel therapeutic tools. We will use this novel tool to modulate gene expression within the PWS locus. This technology can be instrumental to recover the miss-imprinted genes and to rescue the loss of specific neurons in hypothalamus of PWS that causes sleep defects. 

Human intellectual disability is a common and highly heterogeneous paediatric disorder with a frequency of 2 to 3%, with very severe medical and social problems worldwide. Intellectual disability, as other neurodevelopmental disorders, is mainly characterized by the alterations in neuronal dendritic spine development – shape and/or number – suggesting that abnormalities in dendritic spines are a common hallmark for disorders that include deficits in cognition and information processing. Scientific research conducted on these pathologies is essential to fully dissect the molecular networks controlling spine development, remodelling and maintenance, to define the aetiology of the diseases and then to identify a possible therapy. RAB39B is one of the genes responsible for Intellectual Disability associated with Autism Spectrum Disorders. It encodes for a small GTPases that if absent causes defects in proper spine development, remodelling and maturation, reflected by alterations in cognitive performances in a mouse model. The principal aim of the project focuses to define the specific step of the protein cascade affected by the lack of RAB39B, to delineate the molecular mechanism responsible of neuronal dendritic spine remodelling and maturation. Secondly the project aims to modulate the defined step with specific molecules. In this way, we will cover the major gap on intellectual disability, where the complexity of the cellular processes to treat is the answer for the absence of effective therapies.

Le RhoGEF TRIO est connu pour jouer un rôle majeur dans le développement neuronal et dans la fonction cérébrale. De nombreuses mutations de novo dans le gène TRIO ont été identifiées chez des personnes atteintes de troubles du développement neurologique et TRIO est maintenant accepté comme un nouveau gène à risque pour ces troubles. Nous avons précédemment établi la première corrélation phénotype/génotype dans les maladies associées à TRIO, avec une corrélation frappante entre les caractéristiques cliniques des individus et la modulation opposée de l’activité de TRIO ciblant différents domaines de la protéine. Les mutations activatrices sont particulièrement intéressantes, car elles sont retrouvées de manière récurrente chez les patients et sont associées à une forme sévère de déficience intellectuelle et à une macrocéphalie, ce qui indique leur importance dans l’étiologie de la maladie. Pourtant, on ignore encore comment les perturbations de l’activité de TRIO par les mutations pourraient provoquer une déficience intellectuelle.  Nous avons conçu le premier modèle de souris qui exprime l’une des variantes activatrices les plus répandues chez les patients  afin d’avoir un modèle de la maladie. Nous pensons que ce nouveau modèle de souris permettra de mieux comprendre comment ce type de mutations dans le gène TRIO perturbe le développement neuronal. L’objectif global de ce projet est de caractériser le phénotype des souris TRIO au niveau comportemental, cellulaire et moléculaire. A long terme, l’identification des voies de signalisation perturbées par cette mutation nous permettra de développer une approche pharmacologique comme potentielle stratégie thérapeutique pour ces maladies complexes. 

Loss of a copy of the SHANK3 gene is the cause of Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder. The biological basis of PMS is still unclear and, at the moment, there are no approved treatments that tackle the symptomatology of these patients. Protein synthesis is essential for neuronal functions and alteration in protein synthesis have been found in different neurodevelopmental disorder. Our preliminary results obtained studying mice and human neurons derived from PMS patients stem cells suggest that absence of Shank3 leads to a reduction in protein synthesis in neurons that might be the cause of some behavioral abnormalities displayed by PMS patients. In this project we aim to clarify at the molecular level how Shank3 affect protein synthesis. The results of our study will allow to identify new possible molecular target to develop new treatments for PMS patients.

Down Syndrome (DS) phenotypes are thought to result due to heightened expression levels. There are ‎numerous genes that are expressed at higher levels, but which contribute to the phenotypic deficits and ‎which organs they primarily affect is not understood at all. Within the framework of this pilot project, we ‎will use a simple worm as the animal model system and systematically study how increased levels of ‎major genes affects neurodevelopment. For this, we will use state-of-the-art experimental techniques to ‎reveal the fine changes taking place due to protein overexpression. Notably, individuals with DS are ‎typically diagnosed several years after birth, when major neurodevelopmental processes completed. ‎Thus, new therapeutic approaches need to focus on improving deficits at the post development stage. ‎For this, we carefully designed the experimental system such that we can restore the elevated ‎expression to normal levels at the adult stage of the animal. These experiments will hopefully reveal ‎whether it is possible to improve the observed phenotypes by interfering with gene expression levels, and ‎shed light on new molecular mechanisms that will ultimately lead to novel therapeutic prospects.‎

Acute leukaemia is the most common type of cancer seen in children. Although treatments and outcomes have improved remarkably, leukaemia remains the second highest cause of death by cancer in children. Furthermore, many children still suffer from treatment toxicity or develop relapse. These clinical features are exacerbated in children with Down syndrome (DS), a community that already have higher risks of leukaemia compared to other children. This reflects the critical need for novel therapy for these children with Down syndrome that develop leukaemia, especially for the lymphoid leukaemia named DS-ALL. In this project, we will 1) identify new weaknesses in the leukaemia cells that can be targeted with new drugs, 2) characterize and validate the unique and new sophisticated models of DS-ALL we recently established for preclinical use, and 3) test more than 3000 drugs to identify the best ones that could be next pushed towards clinical trials. Altogether, this study is designed to build a workflow that will facilitate the rapid translation of new treatment strategies into the clinic, with the ultimate goal of improving quality of care and long-term outcomes for children with DS that developed leukaemia.

Intellectual disabilities (ID) are neurodevelopmental disorders that affect 1-3% of the population and are characterized by below-average general intellectual dysfunction, with significant limitations in adaptive functions. The causes of ID are heterogeneous, and IDs of genetic origin represent about 30% of cases. The last few years have witnessed a remarkable acceleration in the understanding of the genetic factors involved in IDs and many responsible genes have been identified. However, the link between gene mutations and cognitive dysfunction remains poorly understood. Among genetic disorders, the Coffin-Lowry syndrome (CLS) is a rare disorder characterized by severe ID due to mutations in the RSK2 gene located on the X chromosome. To date, there is no specific preventive or curative treatment for this CLS. For several years, our research team was directed at characterizing the functions of the RSK2 protein and the cellular bases and physiopathological mechanisms at the origin of CLS. For this, a Knock-Out (KO) mouse that does no express the RSK2 protein (Rsk2-KO mouse) was generated. Since IDs are often associated with developmental disorders, we recently studied postnatal development of the brain of this mouse model, and notably development of the hippocampus and cerebellum, brain structures important for cognitive functions. Our work identified a delay in brain development appearing during postnatal development and affecting, in particular, hippocampal and cerebellar development. In parallel, juvenile Rsk2-KO mice displayed transient delays in sensorimotor development and long-lasting cognitive alterations. In this novel project, we propose to assess a therapeutic approach based on specific pharmacological and behavioural interventions, delivered during the postnatal period, in order to rescue the molecular and cellular defects in hippocampus and cerebellum, and prevent, in fine, the establishment of long-term cognitive alterations in the mouse model of CLS.

Hypothalamic dysfunction and defects in brain maturation are involved in the pathophysiology of PWS and particularly impaired oxytocin (OT) network. Deficit of OT explains suckling and swallowing defects of neonates with PWS with high risk of failure to thrive and chocking. We implemented since 2009 a research programme on OT in PWS in infants, children and adults. We more recently focused on infants as early treatment in life may mitigate the severity of the disease (2 studies 2011-2014) and completed in 2021 a European phase III clinical trial in 52 infants showing promising results. In the context of obtaining marketing authorisation of OT in infants with PWS, considering that intranasal administration of OT in infants might have long-term effects by modulating brain plasticity, the EMA requested to follow the treated infants until 4 years of age particularly regarding tolerance and safety issues. For this reason, we started the OTBB3 FOLLOW UP study sponsored by the CHU of Toulouse and coordinated by the reference centre of the CHU of Toulouse (Coordinator Pr M Tauber) It is a prospective, multicentre, interventional study to evaluate the long-term safety profile of early intranasal OT administration and to assess differences at the same age between two cohorts of children with PWS, early OT-exposed and non-exposed, each year until 4 years of age, regarding the evolution/severity of the disease and its associated comorbidities. Biomarkers will also be studied (hormone levels, epigenetic and gut microbiota). Since September 2021, all children (40 OT-exposed and 23non-exposed) have been included and 68% of visits are done or planned until August 2023. Yearly analyses have been required by the EMA and the second one is ongoing. The current demand of funding is to complete the OTBB3 FOLLOW UP study in order to achieve the 53 remaining visits from September 2023-2025, complete the biomarkers analyse, write the intermediate report and made the statistical analysis.

Down syndrome (DS) or trisomy 21 (T21) is a genetic condition characterized by the presence of an extra chromosome 21, which can result in intellectual disability. In addition to this, DS individuals may also experience symptoms related to inflammation and infection. Our primary objective is to determine the frequency of these symptoms, how they affect patients’ quality of life, and investigate the biological mechanisms underlying this scenario. Baricitinib, a specific small molecule inhibitor, has shown effectiveness in treating patients with mutations in the STAT1 protein, resulting in a gain of function (GOF) and increased inflammation. We aim to identify specific genes and proteins that are altered in both DS and STAT1 GOF patients, which will help to establish a biological connection between the two conditions. This approach may aid in the selection of DS patients who could potentially benefit from treatment with Baricitinib. In summary, our study aims to add and advance knowledge on unresolved aspects of Down syndrome (DS). We aim to investigate immune alterations present in DS individuals and their relationship to symptom development. Additionally, we seek to identify which DS patients may benefit from a treatment previously shown to be effective in treating STAT1 GOF patients. The findings from this study could serve as the first step for future clinical trials, ultimately improving the quality of life for patients with DS and autoimmune diseases.

This will be the 20th edition of the Workshop. In organizing this Workshop, we will bring together basic and clinical researchers. Participants at these meetings include biologists, medical geneticists, pharmacologists, neurophysiologists, neuropathologists, neurologists, psychiatrists and experts in clinical trials.  The Workshop’s format promotes interdisciplinary interactions between investigators at all levels of their careers and is designed to maximize productive discussion among participants. This Workshop will bring together investigators from academia as well as pharma and biotech industry, studying a broad variety of neurodevelopmental disorders. The 2023 Workshop is likely to be significant and fruitful because 1) participants have not gathered in this way since the beginning of the COVID-19 pandemic and 2) the field is at a stage where investigators have learned a great deal from a cycle of clinical trials and basic studies and are fine-tuning their approaches. To facilitate interactions, we plan to host all participants at one single location, the Lanier Islands resort, close to Atlanta, Georgia. The Scientific Committee of the Workshop will select presentations so that mainly unpublished research at the forefront of knowledge is presented, both orally and in poster sessions.  To promote discussion and collaboration, ample time is provided between sessions.

The autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by heterogenous clinical manifestations that is the outcome of a complex interaction of predisposition genetic factors and environmental insults. Copy number variations (CNVs) of a gene produces variable dosages of a given gene and represent a large number of highly penetrant rare variants of parental origin associated with ASD risk. CNVs of the cytoplasmic FMR1-interacting protein 1 (CYFIP1) gene have been associate with ASD. Moreover, CYFIP1 gene maps in the 15q11.2 chromosomal region associated with the Prader-Willi syndrome (PWS) and Angelman syndrome (AS), two rare NDD associated with ASD. Infections during pregnancy, also referred to as maternal immune activation (MIA), represent a risk factor for ASD in the offspring. Microglia are the primary innate immune cells of the brain and have recently been implicated in the neuropathological defects of MIA offspring. To date, it is still poorly explored the interaction between a predisposing genetic background with environmental insults in the context of ASD. This project aims to fill this gap by pursuing two main objectives: 1- to evaluate the effects of MIA on the autism-like behaviors of mice expressing reduced levels of Cyfip1 protein, 2- to investigate whether a specific brain resident cell population, the microglia, are involved in the neuropathological effects of the interaction between Cyfip1 gene expression dosage and MIA insult. The final goal of this project is to identify microglia-specific molecules that can be targeted to provide a personalized therapeutic approach in ASD. 

We aim to test a new, innovative RNA technology as therapeutic treatment of 22q11.2DS. These RNA molecules, named SINEUPs, are able to selectively increase the expression of the protein of interest. In 22q11-2DS, a portion of the genome of an individual is deleted in one of its two copies. Since this region contains a number of genes normally involved in brain function, adults can develop schizophrenia. The lack of one of the two copies of these genes led to a 50% decrease of their protein expression and therefore to neuronal dysfunction. By taking advantage of SINEUP technology, we aim to synthesize a molecule able to restore the normal expression of three hemideleted genes crucial for brain function. These experiments will be carried out in adult mice that present the same genetic condition as humans with 22q11.2DS. These preclinical data will be instrumental for a future clinical trial in young adult patients.