The widespread hope for a new era of

The widespread hope for a new era of prevention and treatment for chronic neurological disorders, such as stroke, Alzheimer\'s disease, and Parkinson\'s disease, will likely depend on the discovery of new CNS drugs. However, currently over 99% of candidate CNS drugs fail in clinical tests because of side effects and/or an inability to cross the BBB (Alavijeh et al., 2005). Our human iPSC-derived BBB shows promise as a model for CNS drug development at the pre-clinical stage. BBB models constructed from CNS disease patient-specific iPSCs should also provide new insights into how vascular dysfunction contributes to CNS diseases.
Experimental Procedures
Author Contributions
Acknowledgments We thank the Division of Electron Microscopic Study, Center for Anatomical Studies, Graduate School of Medicine, Kyoto University for helping with the transmission electron microscopy analysis, Dr. A. Ota for providing the drugs, and Dr. P. Karagiannis for critical reading of the manuscript. This study was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan (16K19033), Japan Agency for Medical Research and Development (AMED), the Program for Intractable Diseases Research Utilizing Disease-Specific iPS Cells from AMED, Research Project for Practical Applications of Regenerative Medicine from AMED, Core Center for iPS Cell Research, Research Center Network for Realization of Regenerative Medicine from AMED, Takeda Science Foundation, and iPS Cell Research Fund.
Introduction Frontotemporal dementia (FTD) is the second most common form of early-onset (<65 years) dementia, accounting for 5%–8% of total dementia cases. FTD is a neurodegenerative disorder with cognitive impairment affecting the frontal and/or temporal lobes of the akt pathway associated with progressive brain atrophy (Rossor et al., 2010). FTD is clinically, neuropathologically, and genetically heterogeneous. One gene affected in familial cases is the charged multivesicular body protein 2B (CHMP2B) located on chromosome 3 (FTD3). Patients display global cortical and central brain atrophies, with no apparent amyloid plaque formation or conclusive hyperphosphorylated tau aggregates (Isaacs et al., 2011). Early behavioral changes include apathy, restlessness, disinhibition, and hyperorality. Late-stage behavioral changes include stereotype behavior, mutism, and dystonia (Isaacs et al., 2011). CHMP2B is a component of the endosomal sorting complex required for transport III (ESCRT-III) complex, which facilitates recycling or degradation of cell surface receptors (Chassefeyre et al., 2015). As such, the FTD3-causing mutation of CHMP2B affects functionality of the endosome. Mouse and Drosophila FTD3 animal models have yielded valuable in vivo insights into the dysfunction of the endosomal lysosomal system and pathologic progression (Ahmad et al., 2009; Ghazi-Noori et al., 2012). However, transgene integration and species-specific differences may contribute to observed phenotypes in such models. Hence, there is an emerging need for human FTD3 models. In addition, studying how CHMP2B, as a rare mutation, contributes to neurodegenerative disorders has not yet attracted broader attention. Consequently, a CHMP2B mutant cellular model could provide further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in neurodegenerative diseases and thereby linking different forms of neurodegeneration. The availability of viable neurons from patient brains, at least in part, limits the investigation of the mechanism of neurodegenerative pathogenesis. In this context, human-induced pluripotent stem cells (iPSCs) provide invaluable access to study the disease progression in neurons derived from patient iPSCs and facilitate the development of new therapies (Ehrlich et al., 2015; Rasmussen et al., 2014). Meanwhile, recent advances of state-of-the-art genome engineering technique CRISPR/Cas9 (Ran et al., 2013) have had a tremendous impact allowing for gene correction in patients who are carriers of disease-causing single-point mutations. Such genetically edited iPSCs are ideal isogenic controls for the patient-derived iPSCs, allowing to precisely dissect the significance of the disease-causing mutation while maintaining the patient\'s own genetic background.