{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:35:49Z","timestamp":1791959749266,"version":"4.3.4"},"reference-count":81,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"755","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,7,10]]},"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>microRNA-96<\/jats:italic>\n                    (\n                    <jats:italic>MIR96<\/jats:italic>\n                    ) cause autosomal dominant deafness-50 (DFNA50), a form of delayed-onset hearing loss. Genome editing has shown efficacy in hearing recovery through intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications, which has not been done. Here, we developed a genome editing therapy for the\n                    <jats:italic>MIR96<\/jats:italic>\n                    mutation 14C&gt;A by screening different CRISPR systems and optimizing Cas9 expression and the sgRNA scaffold for efficient and specific mutation editing. AAV delivery of the KKH variant of\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    Cas9 (SaCas9-KKH) and sgRNA to the cochleae of presymptomatic (3-week-old) and symptomatic (6-week-old) adult\n                    <jats:italic>\n                      Mir96\n                      <jats:sup>14C&gt;A\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mutant mice improved hearing long term, with efficacy increased by injection at a  younger age. Adult inner ear delivery resulted in transient Cas9 expression without evidence of AAV genomic integration, indicating the good safety profile of our in vivo genome editing strategy. We developed a dual-AAV system, including an AAV-sgmiR96-master carrying sgRNAs against all known human\n                    <jats:italic>MIR96<\/jats:italic>\n                    mutations. Because mouse and human\n                    <jats:italic>MIR96<\/jats:italic>\n                    sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lay the foundation for the development of treatment for patients with DFNA50 caused by\n                    <jats:italic>MIR96<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adn0689","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T13:58:30Z","timestamp":1720619910000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8746-5346","authenticated-orcid":true,"given":"Wenliang","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2427-6172","authenticated-orcid":true,"given":"Wan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-569X","authenticated-orcid":true,"given":"Arun Prabhu","family":"Rameshbabu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1421-7791","authenticated-orcid":true,"given":"Ariel Miura","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7411-2214","authenticated-orcid":true,"given":"Stewart","family":"Silver","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3056-198X","authenticated-orcid":true,"given":"Yehree","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2036-7312","authenticated-orcid":true,"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8893-434X","authenticated-orcid":true,"given":"Yilai","family":"Shu","sequence":"additional","affiliation":[{"name":"ENT Institute and Otorhinolaryngology Department of Eye &amp; ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China."},{"name":"Institutes of Biomedical Science, Fudan University, Shanghai 200032, China."},{"name":"NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of Miami School of Medicine, Miami, FL 33136, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-8600","authenticated-orcid":true,"given":"Morag A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Wolfson Sensory, Pain and Regeneration Centre, King\u2019s College London, London WC2R 2LS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-5359","authenticated-orcid":true,"given":"Karen P.","family":"Steel","sequence":"additional","affiliation":[{"name":"Wolfson Sensory, Pain and Regeneration Centre, King\u2019s College London, London WC2R 2LS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1452-4193","authenticated-orcid":true,"given":"Zheng-Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA."},{"name":"Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.22579"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241062"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4533"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz129"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-017-4470-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.005"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618757114"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1016646108"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-21811-1"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr493"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.355"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8417-2-7"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.07.006"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy007"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700501200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114519"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.369"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.047225"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25164"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40476-7"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0500-9"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01124-4"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02311-4"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.67781"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2022.07.016"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.06.015"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay9101"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.02.001"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.12.014"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","unstructured":"A. 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