Implementation of a patient-derived disease model of Phelan McDermid Syndrome for the identification of SHANK3-specific chemical modifiers

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.