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Modeling rare pediatric neurogenetic disorders with IPSCs

1 Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Intensive research has been performed to identify the pathological mechanisms of many pediatric neurogenetic disorders and to identify potential therapeutic targets. Although research into many pediatric neurological disorders has provided tremendous insight into the mechanisms of disease, effective treatments remain elusive. A significant impediment to progress has been a lack of thorough disease models. Transgenic/knockout animal models have been very valuable in determining the mechanisms of many neurogenetic disorders; however, these models cannot always mimic human-specific pathology and can be inadequate in representing human pathogenesis. This can be especially true for diseases of the nervous system. Alternatively, human patient-derived nervous tissue can be dangerous to acquire and difficult to propagate. The development of patient-derived induced pluripotent stem cells (IPSCs) has given researchers a fresh means of modeling these disorders with renewable human cells that can be used to generate neurons and glia. IPSCs are somatic cells that are reprogrammed back to a pluripotent stage, which can provide an unlimited source of human cells possessing patient-specific genetic mutations. Their potential to be differentiated into any cell type enables them to be a flexible platform to investigate neurogenetic disease. Of course, efficient methods for differentiating IPSCs into homogeneous populations of somatic cells must be established to provide the “disease-in-a-dish” systems. We will discuss the current methods for generating IPSC-derived neural cells to model pediatric neurogenetic disorders, as well as provide examples of the disorders that have been studied that include several neurodevelopmental and neurodegenerative disorders (Rett syndrome, spinal muscular atrophy, hereditary spastic paraplegias, and leukodystrophies). In addition, we provide examples on how patient-specific neural cells can be used in therapeutic development with high-throughput drug screening platforms or with correction via genome editing.
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