Investigations into the of etiology neurodegenerative diseases have been frustrated by a lack of access to human tissues, and the limited ability of mouse models to recapitulate complex human nervous system diseases. To address this need we have generated multiple episomally-generated integration-free iPSC from ataxia-telangiectasia [1], ataxia with oculomotor apraxia type 2, and Down syndrome [2] individuals and directed their differentiation into CNS cell types relevant to the disease. In vitro assays that identify functional differences between control and disease neurons combined with transcriptome and CAGE analysis of iPSC and iPSC derived neuronal cells at various times during the differentiation process reveals the temporal changes in gene regulatory networks that underlie specific disease states and can be used to identify novel pathogenic mechanisms, novel therapeutic targets and critical temporal windows in these neurodevelopmental diseases. We will report on how we have used genome editing tools to explore the intra-and inter-chromosomal gene regulatory networks underlying Down Syndrome associated pathologies such as Alzheimer disease [3]. Collectively our research provides evidence that patient specific iPSCs are useful in dissecting the mechanisms of complex human neurological diseases and constitute powerful discovery and drug screening platforms.