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Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen \u03b15(IV)-expressing kidney organoids and confirmed that kidney organoids from <jats:italic>COL4A5<\/jats:italic> mutation-corrected iPSCs restore collagen \u03b15(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.<\/jats:p>","DOI":"10.1038\/s42003-023-05203-4","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T10:02:15Z","timestamp":1695895335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["iPSC-derived type IV collagen \u03b15-expressing kidney organoids model Alport syndrome"],"prefix":"10.1038","volume":"6","author":[{"given":"Ryuichiro","family":"Hirayama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Toyohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeya","family":"Otsuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshikazu","family":"Araoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ichi","family":"Mae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-6030","authenticated-orcid":false,"given":"Tomoko","family":"Horinouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Yamamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-1090","authenticated-orcid":false,"given":"Keisuke","family":"Okita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2619-7441","authenticated-orcid":false,"given":"Akitsu","family":"Hotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumoto","family":"Iijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kandai","family":"Nozu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7238-2763","authenticated-orcid":false,"given":"Kenji","family":"Osafune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"5203_CR1","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1126\/science.2349482","volume":"248","author":"D Barker","year":"1990","unstructured":"Barker, D. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248, 1224\u20131227 (1990).","journal-title":"Science"},{"key":"5203_CR2","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1093\/hmg\/3.8.1269","volume":"3","author":"HH Lemmink","year":"1994","unstructured":"Lemmink, H. H. et al. Mutations in the type IV collagen \u03b13 (COL4A3) gene in autosomal recessive Alport syndrome. Hum. Mol. Genet. 3, 1269\u20131273 (1994).","journal-title":"Hum. Mol. Genet."},{"key":"5203_CR3","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1093\/ndt\/12.8.1595","volume":"12","author":"JA Jefferson","year":"1997","unstructured":"Jefferson, J. A. et al. Autosomal dominant Alport syndrome linked to the type IV collage a3 and a4 genes (COL4A3 and COL4A4). Nephrol. Dial. Transplant. 12, 1595\u20131599 (1997).","journal-title":"Nephrol. Dial. 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T.O. is an employee of Ono Pharmaceutical Co., Ltd. K. Osafune is a founder and member of the scientific advisory boards of iPS Portal, Inc., and a founder and chief scientific advisor of RegeNephro Co., Ltd. T.A. is a founder and scientific advisor of RegeNephro Co., Ltd. S.I.M. is a scientific advisor of RegeNephro Co., Ltd. R.H., T.A. and K. Osafune are the inventors of the iPSC-based disease model for AS (patent application 2021\u2013184043). The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"854"}}