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It is caused by mutations in the\n                    <jats:italic>OCRL<\/jats:italic>\n                    gene, which encodes an inositol 5\u2010phosphatase. The disorder remains incurable, and the pathways underlying the ocular symptoms remain poorly understood, largely due to the lack of appropriate models. In this study, trabecular meshwork cell models of Lowe syndrome were generated to test two distinct gene therapy strategies: a mutation\u2010agnostic\n                    <jats:italic>OCRL<\/jats:italic>\n                    DNA augmentation therapy and a patient\u2010specific CRISPR\u2010mediated gene correction strategy. The results showed that AAV2\u2010OCRL demonstrated the highest transduction efficiency in patient iPSC\u2010derived trabecular meshwork models (iHTM) among the three AAV\u2010OCRL vectors evaluated, establishing it as a promising delivery vector. Targeted CRISPR\u2010based gene therapy restored OCRL enzyme activity and corrected cellular defects in patient iPSC\u2010derived trabecular meshwork cell models. Furthermore, RNA\u2010sequencing analysis of these models revealed dysregulation of extracellular matrix organization, cell adhesion, focal adhesion, and cytoskeletal regulatory pathways, suggesting that disruption of interconnected ECM\u2010adhesion\u2010cytoskeletal networks may contribute to trabecular meshwork dysfunction in Lowe syndrome\u2010associated glaucoma. These findings indicate the feasibility of\n                    <jats:italic>OCRL<\/jats:italic>\n                    gene augmentation and CRISPR\u2010based gene editing in patient\u2010derived ocular models and position AAV2\u2010OCRL as a leading therapeutic candidate for Lowe syndrome.\n                  <\/jats:p>","DOI":"10.1002\/advs.77704","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:41:07Z","timestamp":1789018867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR and Gene Augmentation Rescue Trabecular Meshwork Dysfunction in iPSC Models of Lowe Syndrome"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9801-4917","authenticated-orcid":false,"given":"Siyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5433-5656","authenticated-orcid":false,"given":"Zhiquan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8194-5680","authenticated-orcid":false,"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tia J.","family":"Kowal","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5331-0358","authenticated-orcid":false,"given":"Grzegorz","family":"Walkiewicz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2864-3046","authenticated-orcid":false,"given":"Faruk","family":"Hossen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert M.","family":"Lachman","sequence":"additional","affiliation":[{"name":"Department of Genetics Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqiong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-4765","authenticated-orcid":false,"given":"Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto California USA"},{"name":"Palo Alto Veterans Administration  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467\u2010016\u20103343\u20103"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20101\u201016"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1120672120920544"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010050565"},{"issue":"12","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.cub.2011.05.030","article-title":"The Inositol 5\u2010phosphatase dOCRL Controls PI(4,5)P2 Homeostasis and Is Necessary for Cytokinesis","volume":"21","author":"Kadhi B. 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