environMENTAL

There is an undisputed need for better therapies addressing mental illnesses. However, despite major advances in the understanding of the molecular basis of disorders such as depression, anxiety schizo­phrenia and autism in the past decades, efforts to discover and develop new drugs for neuropsychiatric disorders have remained relatively unsuccessful. The disappointments can be traced to failures in the target identification and target validation effort, as reflected by the poor ability of current cellular and animal models to predict efficacy and side-effects. Here will I discuss how patient-based disease mod­elling can be implemented in the early drug discovery process as a crucial component in addressing current problems.

Autism Spectrum Disorders (ASD) are a heterogeneous group of neurodevelopmental disorders which complicates the identification of an effective therapeutic solution. More than 75 % of people suffering from Phelan McDermid Syndrome (PMS) exhibits ASD symptoms. This rare disease is due to a dele­tion/alteration in chromosome chromosome 22 (22q13) leading to a haploinsufficiency of SHANK3 expression. SHANK3 encodes a scaffolding protein in the postsynaptic density of excitatory synapses. A reduced expression of SHANK3 leads to an alteration in neuron morphology and synapse connectivity via unknown mechanism.
After the identification of a developmental hyperdifferentiation phenotype in patient-derived iPS cells during the first 6-14 days of differentiation into glutamatergic neurons, a fully automated process was developed allowing us to perform a >7000 molecules screening to reverse hyperdifferentiation. Valida­tion of identified hit compounds was performed in a synaptic imaging assay after 28 days of differentia­tion. In summary, we performed phenotypic screening using specific pathological hallmarks of a neuro­developmental disease in patient-derived of cells.

Our twin goals:

• the scientific work of the Human Brain Project(HBP)
• the ongoing development of the state-of-the art Research Infrastructure for brain studie: France Nivelle, Chief Communications and Content Officer, EBRAINS