Impairment of neuronal circuit formation during cortical development has been proposed as a major cause of neurodevelopmental disorders such as autism, epilepsy and intellectual disability. Severe forms of autism are co-morbid with intellectual disability, difficult to treat epilepsy and non-verbal status, and affect about 30% of patients diagnosed with autism. There are to date no current effective bio-therapeutics to treat patients affected by severe autism. Using a combination of genome edited and patient derived induced pluripotent stem cells (iPSC) we hope to gain a better understanding on the underlying mechanisms that could eventually lead to the development of much needed therapeutics for difficult to treat autism.
Endosomal Signaling in autism and intellectual disability The establishment of neuronal circuitry during development depends on the careful orchestration of several cellular processes, including proper neuronal arborization and formation of functional synapses in response to neuronal activity. One major focus of our research will be the study of endosomal signaling in neuronal morphogenesis and synaptogenesis. The endosomal machinery controls receptor trafficking, recycling, degradation, and modulates signaling pathways important for neuronal growth, arborization, and synaptogenesis. Using genome-editing approaches in human iPSC we are targeting endosomal proteins that have been associated with autism and intellectual disability. With this approach we hope to further elucidate common mechanisms in disorders of neuronal connectivity.
Gene-environment interaction in autism spectrum disorders Autism spectrum disorders (ASD) are highly heritable. However, a significant proportion of ASD cases are of complex genetic etiology, an indication that this complexity might reflect the impact of gene-environment interactions. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes associated with autism. This suggests that environmental risk factors for ASD might exert their effect by modulating epigenetic mechanisms that alter neuronal development. We are using genome-editing approaches in human stem cells to determine the neuronal function of chromatin regulatory factors that have been previously associated with higher risk variants in ASD.