Characterization of iPSC-derived neural cells to support PACS2 syndrome treatment development

Neurodevelopmental disorders (NDDs) are heterogenous and usually present with complex etiology. Individuals with these conditions present with cognitive impairment accompanied by lifelong deficits; yet remarkably little is known about their neurological basis. As high as 17% of children are estimated to have a developmental disability and progress for therapy development has been slow. Patients with phosphofurin acidic cluster-sorting protein-2 (PACS2) mutations have even fewer options due the recent discovery of this disease and therefore its relatively understudied status. Current research involving PACS2 mostly concerns either clinical observations or experiments to determine the protein’s function at a basic-science level. This provides extremely valuable background information for understanding the disease, but establishing better disease models would greatly aid our understanding of basic mechanisms and allow the development of novel therapeutic strategies for treatment. A current challenge in the field of developmental neuroscience is the ability to track developing neurons in vivo. Induced pluripotent stem cell (iPSCs) offer the opportunity to work directly with human neurons predisposed to neurological disorders. We aim to establish both iPSCs and iPSC-derived neuronal cells as model system to accelerate PACS2 Syndrome research. Therefore, the overall goal of this proposal is to generate and characterize iPSC lines and iPSC-derived neural cells that in the future will serve as a model to gain insight into the disease mechanisms of PACS2 Syndrome. We plan to use a combination of CRISPR genome editing with stem cell technology to generate and characterize the appropriate iPSC lines, both from patients with PACS2 Syndrome as well as control individuals. Moreover, this work will form the basis of a federal grant application (e.g., NIH R21) by helping narrow down what physiological aspects we should assess in future studies aimed to determine pathological mech