Zhao Xingle, Xu Hongen, Lian Chengyu, Hu Shousen, Zhao Yue, Wang Jia, Zhai Rongqun, Yang Mihuan, Zhang Yuanjing, Lu Wei, Tang Wenxue, Wang Liang
Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Precision Medicine Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Gene Ther. 2025 Aug 21. doi: 10.1038/s41434-025-00558-1.
Vesicular glutamate transporter 3 (VGLUT3) is prominently expressed in the inner hair cells of the cochlea, playing a vital role in auditory signal transmission to the brain. Previous studies have shown that Vglut3 gene knockout in mice causes severe sensorineural hearing loss without affecting hair cell integrity. However, the cochlear structure of the aged Vglut3 remains inadequately explored. In this study, we analyzed the cochlear structure of aged Vglut3 mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia. To explore the potential of gene therapy to restore cochlear structure, we employed AAV8 vectors to express Vglut3 in the cochleae of 5-week-old Vglut3 mice. Twenty-seven weeks post-injection, we conducted a series of experiments to evaluate the efficacy of our gene therapy approach. Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy. Immunohistochemical staining and scanning electron microscopy (SEM) analysis revealed substantial recovery of inner hair cells and stereocilia post-injection. Our findings provide important insights into the development of novel therapeutic strategies for age-related hearing loss.
囊泡谷氨酸转运体3（VGLUT3）在耳蜗的内毛细胞中显著表达，在听觉信号向大脑的传递中起着至关重要的作用。先前的研究表明，小鼠体内Vglut3基因敲除会导致严重的感音神经性听力损失，而不会影响毛细胞的完整性。然而，老年Vglut3小鼠的耳蜗结构仍未得到充分研究。在本研究中，我们分析了老年Vglut3小鼠的耳蜗结构，发现内毛细胞、突触和静纤毛出现了明显退化。为了探索基因治疗恢复耳蜗结构的潜力，我们使用AAV8载体在5周龄的Vglut3小鼠耳蜗中表达Vglut3。注射后27周，我们进行了一系列实验来评估我们的基因治疗方法的疗效。听觉脑干反应（ABR）测试表明基因治疗后听觉功能得到恢复。免疫组织化学染色和扫描电子显微镜（SEM）分析显示注射后内毛细胞和静纤毛有显著恢复。我们的研究结果为开发针对年龄相关性听力损失的新型治疗策略提供了重要见解。
