The autism spectrum disorders (ASDs) comprise a set of neurodevelopmental disorders that are, at best, still poorly understood and, yet, they are the fastest growing developmental disorder in the United States. Analysis of the post-mortem brain has provided some of the most valuable data for advancing our understanding of ASD pathophysiology. In addition, neural stem cells (NSCs) can be harvested from the post- mortem ASD brain, providing a critical tool for the study of ASDs, as detailed examination of the proliferation and differentiation of NSCs derived from ASD brains, compared with those derived from normal brains, is likely to yield important data regarding the etiology of the disease and provide new avenues for therapeutic approaches. The procurement of post-mortem ASD brains, however, has proven to be difficult. Thus, the generation of sufficient numbers of ASD NSC lines has been slow. Recent advances in stem cell research now allow for this difficulty to be overcome. It is now possible to """"""""de-differentiate"""""""" or re-program human fibroblasts to an induced pluripotent stem cell (iPSC) state;that is, a line of stem cells that can differentiate into virtually any tissue cell type, such as brain, can be created from a fibroblast cell. This raises the potential of applying this technology to fibroblasts derived from ASD patients to allow study of resulting NSCs. Since fibroblasts are readily procured, sufficient statistical power for a whole host of studies can be achieved. We will apply the reprogramming technique to both fibroblasts derived from well- characterized patients with autism as well as those derived from normal individuals. Using the recently described gene candidates for reprogramming cells, we will transduce fibroblasts using published methods and characterize their conversion to iPSCs. We will use existing cell lines or cells lines recruited with our collaborators, procured under our stem cell-specific consent, for both the re-programming methodology and the compare and contrast evaluation of resulting cell lines. Specific methodology evaluation will be accomplished using fibroblasts and NSCs, already in our repository, that were derived from the same patients. The implication for the study of the ASDs simply cannot be overstated. Efficient generation of autism NSC lines will allow for studies that have never before been possible. These include (1) studies examining the detailed pathophysiology of the autism neuron, (2) studies of sufficient statistical power that can compare and contrast the effects of autism on neuronal differentiation, and (3) studies of the influence of environmental factors on these processes. Importantly, all data generated will be made available. The lines themselves will also be made available to the scientific community through our existing stem cell repository. This will leverage our efforts for maximal benefit to patients and families affected by autism.

Public Health Relevance

The overall purpose of this project is to overcome a critical barrier in the field of autism research;namely, accessibility to statistically relevant numbers of patient-derived neural tissues. Our novel strategy, which is based on our considerable human neural stem cell (NSC), human embryonic stem cell (ESC), and biorepository experience, is to obtain fibroblasts from specific autism and control patients, derive induced pluripotent stem cells (iPSCs) from the fibroblasts, differentiate NSCs from the iPSCs, characterize and contrast and compare these cells using gene microarray and bioinformatics techniques, and provide the cells to specific autism researchers.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Kau, Alice S
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Children's Hospital of Orange County
United States
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Xie, Yunyao; Schutte, Ryan J; Ng, Nathan N et al. (2018) Reproducible and efficient generation of functionally active neurons from human hiPSCs for preclinical disease modeling. Stem Cell Res 26:84-94
Brick, David J; Nethercott, Hubert E; Montesano, Samantha et al. (2014) The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery. Stem Cells Transl Med 3:1275-86
Kumari, Daman; Bhattacharya, Aditi; Nadel, Jeffrey et al. (2014) Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum Mutat 35:1485-94
Stover, Alexander E; Brick, David J; Nethercott, Hubert E et al. (2013) Process-based expansion and neural differentiation of human pluripotent stem cells for transplantation and disease modeling. J Neurosci Res 91:1247-62
Wesselschmidt, Robin L; Schwartz, Philip H (2011) The stem cell laboratory: design, equipment, and oversight. Methods Mol Biol 767:3-13
Stover, Alexander E; Schwartz, Philip H (2011) The generation of embryoid bodies from feeder-based or feeder-free human pluripotent stem cell cultures. Methods Mol Biol 767:391-8
Nethercott, Hubert E; Brick, David J; Schwartz, Philip H (2011) Derivation of induced pluripotent stem cells by lentiviral transduction. Methods Mol Biol 767:67-85
Nethercott, Hubert E; Brick, David J; Schwartz, Philip H (2011) Immunocytochemical analysis of human pluripotent stem cells. Methods Mol Biol 767:201-20
Marei, Hany E S; Althani, Asma; Afifi, Nahla et al. (2011) Gene expression profiling of embryonic human neural stem cells and dopaminergic neurons from adult human substantia nigra. PLoS One 6:e28420
Schwartz, Philip H; Brick, David J; Nethercott, Hubert E et al. (2011) Traditional human embryonic stem cell culture. Methods Mol Biol 767:107-23

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