Amariutei, A.E. orcid.org/0000-0001-5803-1166, Webb, S., Carlton, A.J. orcid.org/0000-0002-1054-3901 et al. (10 more authors) (2025) Adeno-associated virus-based rescue of Myo7a expression restores hair-cell function and improves hearing thresholds in a USH1B mouse strain. The Journal of Physiology. ISSN: 0022-3751
Abstract
Mutations in MYO7A, 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-rich stereocilia. Shaker-1 mutant mice (Myo7aSh1/Sh1), 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 shaker-1 mutation prevented both inner hair cells (IHCs) and outer hair cells (OHCs) from acquiring their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7aSh1/Sh1 mice using dual-adeno-associated virus 8 (AAV8)-Myo7a or dual-AAV9-PhP.eB-Myo7a, 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 20–30 dB in hearing thresholds across most frequencies. These results support dual AAV-induced gene replacement therapy as an effective strategy to recover hair-cell function in Myo7aSh1/Sh1 mice.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ |
Keywords: | cochlea; deafness; gene-based therapy; hair cell; ion channels; mechanoelectrical transduction; myosin motor; ribbon synapses |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Date Deposited: | 29 Sep 2025 14:23 |
Last Modified: | 29 Sep 2025 14:23 |
Status: | Published online |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1113/jp289526 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:232341 |