{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:21:44Z","timestamp":1787768504114,"version":"build-2784847793"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"864","funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY028167"],"award-info":[{"award-number":["R01EY028167"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY030183"],"award-info":[{"award-number":["R01EY030183"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY033192"],"award-info":[{"award-number":["R01EY033192"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY032116"],"award-info":[{"award-number":["R01EY032116"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY035887"],"award-info":[{"award-number":["R01EY035887"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30EY025585"],"award-info":[{"award-number":["P30EY025585"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR064200"],"award-info":[{"award-number":["R01AR064200"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["NIH UH3 DE027695"],"award-info":[{"award-number":["NIH UH3 DE027695"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008091","name":"University of Rochester","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008091","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Forebattn Foundation"},{"name":"Mangurian Foundation"},{"DOI":"10.13039\/100018313","name":"Cleveland Eye Bank Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018313","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dale and Lois Marks & Family"},{"name":"Timken foundation"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,8,26]]},"abstract":"<jats:p>\n                    Disruption of the photoreceptor\u2013retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, is a pathological hallmark of several neurodegenerative and retinal diseases, including lysosomal storage disorders like juvenile neuronal ceroid lipofuscinosis (CLN3) disease. However, in vitro stem cell models that enable investigation of the photoreceptor-RPE interface are lacking. Here, we developed a 3D human pluripotent stem cell\u2013derived retina organoid\u2013RPE (hPSC-RO-RPE) model to investigate the photoreceptor-RPE interface in healthy and diseased tissues. Using this 3D hPSC-RO-RPE retina model, we showed that the most common disease-causing CLN3 mutation (\n                    <jats:italic toggle=\"yes\">CLN3<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:italic toggle=\"yes\">ex7-8<\/jats:italic>\n                    <\/jats:sup>\n                    ) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus\n                    <jats:italic toggle=\"yes\">CLN3<\/jats:italic>\n                    mutant (\n                    <jats:italic toggle=\"yes\">CLN3<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:italic toggle=\"yes\">ex7-8<\/jats:italic>\n                    <\/jats:sup>\n                    ) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 disease pathobiology, and (ii) we showed a cell autonomous role of the RPE dysfunction in promoting POS loss\/retina degeneration in CLN3 disease. We validated the molecular and structural changes observed in the\n                    <jats:italic toggle=\"yes\">CLN3<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:italic toggle=\"yes\">ex7-8<\/jats:italic>\n                    <\/jats:sup>\n                    hPSC-RO-RPE model in the CLN3 miniswine model (\n                    <jats:italic toggle=\"yes\">CLN3<\/jats:italic>\n                    <jats:sup>\n                      \u0394\n                      <jats:italic toggle=\"yes\">ex7-8<\/jats:italic>\n                    <\/jats:sup>\n                    ) and donor eyes from two patients with CLN3 disease. High-resolution retinal imaging of the living eye in two patients with CLN3 disease suggested decreased RPE autofluorescence in early-stage CLN3 disease. Treatment with recombinant human acid ceramidase (rhAC) ameliorated photoreceptor degeneration in both the CLN3 disease RO-RPE model and CLN3 miniswine eyes. These findings suggest that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ady7616","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:00:27Z","timestamp":1787767227000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A 3D human retina model reveals a non\u2013cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6911-7870","authenticated-orcid":true,"given":"Jimin","family":"Han","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5091-0527","authenticated-orcid":true,"given":"Nathaniel","family":"Foley","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1561-4622","authenticated-orcid":true,"given":"Sonal","family":"Dalvi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet A. H.","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-8674","authenticated-orcid":true,"given":"Fesahat","family":"Emira Dogrul","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6233-5357","authenticated-orcid":true,"given":"Amit","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lal Krishan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1978-7339","authenticated-orcid":true,"given":"Chad A.","family":"Galloway","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1875-3994","authenticated-orcid":true,"given":"Ajay Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0384-2645","authenticated-orcid":true,"given":"Leah M.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashoda","family":"Subedi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA."},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, NY 14642, USA."},{"name":"Center for Visual Science, University of Rochester, Rochester, NY 14642, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5784-2311","authenticated-orcid":true,"family":"Kevin C. 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E.","year":"2019","unstructured":"E. E. Capowski, K. Samimi, S. J. Mayerl, M. J. Phillips, I. Pinilla, S. E. Howden, J. Saha, A. D. Jansen, K. L. Edwards, L. D. Jager, K. Barlow, R. Valiauga, Z. Erlichman, A. Hagstrom, D. Sinha, V. M. Sluch, X. Chamling, D. J. Zack, M. C. Skala, D. M. Gamm, Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. 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K.","year":"2016","unstructured":"S. K. Bhatia, A. Rashid, M. A. Chrenek, Q. Zhang, B. B. Bruce, M. Klein, J. H. Boatright, Y. Jiang, H. E. Grossniklaus, J. M. Nickerson, Analysis of RPE morphometry in human eyes. Mol. Vis. 22, 898\u2013916 (2016).","journal-title":"Mol. Vis."},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710430114"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.09.006"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200903924"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.08.055"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.200901808"},{"key":"e_1_3_2_55_2","doi-asserted-by":"crossref","unstructured":"T. Zarembinski A. Skardal \u201cHyStem\u00ae: A unique clinical grade hydrogel for present and future medical applications \u201d in Hydrogels - Smart Materials for Biomedical Applications (IntechOpen 2018).","DOI":"10.5772\/intechopen.81344"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.progpolymsci.2020.101243"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.ady7616","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:00:50Z","timestamp":1787767250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.ady7616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":55,"journal-issue":{"issue":"864","published-print":{"date-parts":[[2026,8,26]]}},"alternative-id":["10.1126\/scitranslmed.ady7616"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.ady7616","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"2025-05-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eady7616"}}