{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:04:11Z","timestamp":1789473851655,"version":"build-2803163510"},"reference-count":93,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"\n Abstract<\/jats:title>\n \n Mutations in\n MYO7A<\/jats:italic>\n , the gene encoding the unconventional myosin 7a, cause hereditary deafness in mice and humans. In the cochlea, MYO7A is present in the sensory hair cells from embryonic stages of development, and plays a critical role in the development and maintenance of the mechanosensitive hair bundles composed of actin\u2010rich stereocilia.\n Shaker\u20101<\/jats:italic>\n mutant mice (\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n ), the murine model of Usher 1B syndrome, exhibit a progressive loss of the stereocilia, subsequent degeneration of the sensory epithelium and ultimately profound deafness. In addition to the hair bundle defects, we found that the\n shaker\u20101<\/jats:italic>\n mutation prevented both inner hair cells (IHCs) and outer hair cells (OHCs) from acquiring their fully mature basolateral current profile. Delivering exogenous\n Myo7a<\/jats:italic>\n to newborn\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n mice using dual\u2010adeno\u2010associated virus 8 (AAV8)\u2010\n Myo7a<\/jats:italic>\n or dual\u2010AAV9\u2010PhP.eB\u2010\n Myo7a<\/jats:italic>\n , which primarily target IHCs, led to a substantial rescue of their hair bundle structure. The rescued bundles regained their ability to generate mechanoelectrical transducer (MET) currents in response to fluid jet displacement. Although the average MET current was smaller than in control IHCs, the normal resting open probability of the MET channel was fully restored. The IHCs of the treated cochlea also regained a mature basolateral membrane current profile. Functionally, rescue of the IHC structure and function, but not that of OHCs, leads to an average improvement of 20\u201330\u00a0dB in hearing thresholds across most frequencies. These results support dual AAV\u2010induced gene replacement therapy as an effective strategy to recover hair\u2010cell function in\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n mice.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Shaker\u20101<\/jats:italic>\n mutant mice (\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n ), which carry a mutation in the unconventional myosin MYO7A and are the murine model of Usher 1B syndrome, become profoundly deaf at 1\u00a0month of age or soon after.\n <\/jats:p>\n <\/jats:list-item>\n \n In the mammalian cochlea, MYO7A is expressed in the hair cells, including within their actin\u2010rich stereociliary bundles.<\/jats:p>\n <\/jats:list-item>\n \n \n We show that hair cells of\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n mice progressively lose their transducing stereocilia and mechanoelectrical transduction, and fail to acquire their fully mature basolateral current profile.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Delivering exogenous\n Myo7a<\/jats:italic>\n to newborn\n \n Myo7a\n Sh1\/Sh1<\/jats:sup>\n <\/jats:italic>\n mice using dual\u2010adeno\u2010associated virus (AAVs) led to a substantial rescue of the bundle structure and function of inner hair cells, including mechanoelectrical transduction.\n <\/jats:p>\n <\/jats:list-item>\n \n This functional rescue led to a 20\u201330\u00a0dB improvement in hearing thresholds across most frequencies.<\/jats:p>\n <\/jats:list-item>\n \n \n These results support dual AAV\u2010induced gene replacement therapy as an effective strategy to recover the hair\u2010cell function in\n \n Myo7a\n Sh1\/Sh1\u00a0<\/jats:sup>\n <\/jats:italic>\n mice.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289526","type":"journal-article","created":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T01:10:40Z","timestamp":1759021840000},"page":"7171-7188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Adeno\u2010associated virus\u2010based rescue of\n Myo7a<\/i>\n expression restores hair\u2010cell function and improves hearing thresholds in a\n USH1B<\/i>\n mouse strain"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5803-1166","authenticated-orcid":false,"given":"Ana E.","family":"Amariutei","sequence":"first","affiliation":[{"name":"School of Biosciences University of Sheffield Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Webb","sequence":"additional","affiliation":[{"name":"School of Biosciences University of Sheffield Sheffield 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