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Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose\u2014and ensuring reproducibility, scalability, and accessibility\u2014will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.<\/jats:p>","DOI":"10.1177\/15473287261481004","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T11:00:31Z","timestamp":1787396431000},"page":"413-417","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point"],"prefix":"10.1177","volume":"35","author":[{"given":"Aline M.A.","family":"Martins","sequence":"first","affiliation":[{"name":"Integrated Space Stem Cell Orbital Research Center, Sanford Stem Cell Institute, University of California San Diego, La Jolla, California, USA."},{"name":"Department of Regenerative Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alysson R.","family":"Muotri","sequence":"additional","affiliation":[{"name":"Integrated Space Stem Cell Orbital Research Center, Sanford Stem Cell Institute, University of California San Diego, La Jolla, California, USA."},{"name":"Department of Pediatrics and Cellular &amp; 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