Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model
Abstract Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c kno...
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2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410063 |
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| author | Weinan Du Jun Huang Aizhen Zhang Fangfang Zhao Tianwen Chen Quinn M. McDermott Tony Zheng Haibo Wang Rongli Zhang Xiaolin Zhang Jerome Allison Hong Zhu Wu Zhou Qing Yin Zheng |
| author_facet | Weinan Du Jun Huang Aizhen Zhang Fangfang Zhao Tianwen Chen Quinn M. McDermott Tony Zheng Haibo Wang Rongli Zhang Xiaolin Zhang Jerome Allison Hong Zhu Wu Zhou Qing Yin Zheng |
| author_sort | Weinan Du |
| collection | DOAJ |
| description | Abstract Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c knockout (KO) mouse model displaying these characteristic deficits is generated in our laboratory. To examine gene replacement therapy (GT) in this model, a synthetic adeno‐associated viral vector, Anc80L65, driving harmonin expression is administered, to the inner ears of Ush1c KO mice at postnatal day 2 (P2). Remarkably, this single treatment significantly improved auditory brainstem response (ABR) thresholds and balance motor function at 1 month post‐injection, with these effects persisting for up to 10 months. At 12 months post‐treatment, the vestibular function is assessed using the vestibular‐ocular reflexes (VOR) and single vestibular afferent recordings. The GT treatment significantly restored both the canal and otolith VORs and increased vestibular afferent spontaneous firing rates and responses to head rotation and translation. These findings provide the first evidence of long‐lasting restoration of both the auditory and vestibular functions by GT in a novel mouse model of Usher syndrome, highlighting the potential of GT for treating deficits associated with USH1C. |
| format | Article |
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| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2a9025a0831a4d6e8e0a1d2c26547ca62025-08-20T03:40:00ZengWileyAdvanced Science2198-38442025-08-011229n/an/a10.1002/advs.202410063Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse ModelWeinan Du0Jun Huang1Aizhen Zhang2Fangfang Zhao3Tianwen Chen4Quinn M. McDermott5Tony Zheng6Haibo Wang7Rongli Zhang8Xiaolin Zhang9Jerome Allison10Hong Zhu11Wu Zhou12Qing Yin Zheng13Department of Otolaryngology Case Western Reserve University Cleveland OH 44106 USADepartment of Otolaryngology‐Head and Neck Surgery University of Mississippi Medical Center Jackson MS 39216 USADepartment of Otolaryngology Case Western Reserve University Cleveland OH 44106 USADepartment of Otolaryngology Case Western Reserve University Cleveland OH 44106 USADepartment of Otolaryngology‐Head and Neck Surgery University of Mississippi Medical Center Jackson MS 39216 USADepartment of Otolaryngology Case Western Reserve University Cleveland OH 44106 USADepartment of Otolaryngology Case Western Reserve University Cleveland OH 44106 USADepartment of Otolaryngology‐Head and Neck Surgery Shandong Provincial ENT Hospital Shandong University Jinan Shandong 250022 ChinaCase Cardiovascular Research Institute Case Western Reserve University School of Medicine Cleveland OH 44106 USADepartment of Otolaryngology Binzhou Medical University Hospital Binzhou 256603 ChinaDepartment of Otolaryngology‐Head and Neck Surgery University of Mississippi Medical Center Jackson MS 39216 USADepartment of Otolaryngology‐Head and Neck Surgery University of Mississippi Medical Center Jackson MS 39216 USADepartment of Otolaryngology‐Head and Neck Surgery University of Mississippi Medical Center Jackson MS 39216 USADepartment of Otolaryngology Case Western Reserve University Cleveland OH 44106 USAAbstract Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c knockout (KO) mouse model displaying these characteristic deficits is generated in our laboratory. To examine gene replacement therapy (GT) in this model, a synthetic adeno‐associated viral vector, Anc80L65, driving harmonin expression is administered, to the inner ears of Ush1c KO mice at postnatal day 2 (P2). Remarkably, this single treatment significantly improved auditory brainstem response (ABR) thresholds and balance motor function at 1 month post‐injection, with these effects persisting for up to 10 months. At 12 months post‐treatment, the vestibular function is assessed using the vestibular‐ocular reflexes (VOR) and single vestibular afferent recordings. The GT treatment significantly restored both the canal and otolith VORs and increased vestibular afferent spontaneous firing rates and responses to head rotation and translation. These findings provide the first evidence of long‐lasting restoration of both the auditory and vestibular functions by GT in a novel mouse model of Usher syndrome, highlighting the potential of GT for treating deficits associated with USH1C.https://doi.org/10.1002/advs.202410063USH1Charmoningene replacement therapyauditoryvestibularAAV |
| spellingShingle | Weinan Du Jun Huang Aizhen Zhang Fangfang Zhao Tianwen Chen Quinn M. McDermott Tony Zheng Haibo Wang Rongli Zhang Xiaolin Zhang Jerome Allison Hong Zhu Wu Zhou Qing Yin Zheng Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model Advanced Science USH1C harmonin gene replacement therapy auditory vestibular AAV |
| title | Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model |
| title_full | Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model |
| title_fullStr | Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model |
| title_full_unstemmed | Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model |
| title_short | Long‐Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model |
| title_sort | long lasting auditory and vestibular recovery following gene replacement therapy in a novel usher syndrome type 1c mouse model |
| topic | USH1C harmonin gene replacement therapy auditory vestibular AAV |
| url | https://doi.org/10.1002/advs.202410063 |
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