{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:09:31Z","timestamp":1792634971742,"version":"4.5.0"},"reference-count":38,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"798","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,5,14]]},"abstract":"<jats:p>\n            Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)\u2013mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes in adult nonhuman primates (NHPs) to identify capsids with potent transduction of key brain tissues, including ependyma, after intracerebroventricular injection. Through these screens, we identified an AAV capsid, AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            , with markedly increased potency in transducing ependymal cells and cerebral neurons in NHPs. AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            \u2019s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells. To apply AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            to the treatment of ceroid lipofuscinosis type 2 disease, a lysosomal storage disorder caused by loss-of-function mutations in\n            <jats:italic toggle=\"yes\">tripeptidyl-peptidase 1<\/jats:italic>\n            (\n            <jats:italic toggle=\"yes\">TPP1<\/jats:italic>\n            ), we used the capsid to package the human\n            <jats:italic toggle=\"yes\">TPP1<\/jats:italic>\n            transgene (AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            .hTPP1) and delivered the construct by intracerebroventricular injection into mice lacking TPP1 activity. AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            provided robust and therapeutically relevant TPP1 protein concentrations in these mice, significantly improving tremor and life span. In NHPs, high cerebrospinal fluid (CSF) TPP1 concentrations were achieved after intracerebroventricular delivery of AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            .hTPP1 at a total dose of 1 \u00d7 10\n            <jats:sup>12<\/jats:sup>\n            viral genomes, which was more than 30\u00d7 lower than previously reported doses in NHPs. These results suggest that AAV-Ep\n            <jats:sup>+<\/jats:sup>\n            may be a potent vector for gene therapy applications where CSF protein expression is required.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adr2531","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T17:58:37Z","timestamp":1747245517000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7101-3544","authenticated-orcid":true,"given":"Luis","family":"Tecedor","sequence":"first","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6473-8457","authenticated-orcid":true,"given":"Yong Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6243-9455","authenticated-orcid":true,"given":"David E.","family":"Leib","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Latus Bio, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1620-5855","authenticated-orcid":true,"given":"Paul T.","family":"Ranum","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Latus Bio, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9055-6874","authenticated-orcid":true,"given":"Megan S.","family":"Keiser","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, NeuroTech Institute, Ohio State University, Columbus, OH 43210 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-5979","authenticated-orcid":true,"given":"Brian C.","family":"Lewandowski","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-5437","authenticated-orcid":true,"given":"Elli M.","family":"Carrell","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Lysenko","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Icnelia","family":"Huerta-Ocampo","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakshi","family":"Arora","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congsheng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-6290","authenticated-orcid":true,"given":"Beverly L.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0025-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11121775"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.06.019"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)45842-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2006.01.006"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2676-05.2006"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)91275-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/mp300495e"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2936-05.2005"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5333.1802"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0730700.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302549"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac6191"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2020.167"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/01926233221101309"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2020.116"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.07.020"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.01.013"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3428"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007000"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2729-04.2004"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb5413"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.11.049"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.07.017"},{"key":"e_1_3_2_27_2","doi-asserted-by":"crossref","unstructured":"D. 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Davidson Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates. bioRxiv 592211 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.05.02.592211.","DOI":"10.1101\/2024.05.02.592211"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1108-04.2005"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.01.003"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2014.51"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2023.067"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2016.10.022"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.870799"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.10.007"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201809824"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02555-y"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.948"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.05.072"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adr2531","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T17:58:56Z","timestamp":1747245536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adr2531"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,14]]},"references-count":38,"journal-issue":{"issue":"798","published-print":{"date-parts":[[2025,5,14]]}},"alternative-id":["10.1126\/scitranslmed.adr2531"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adr2531","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,14]]},"assertion":[{"value":"2024-06-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-08","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr2531"}}