Zhang Ting, Zhai Rongqun, Liu Mengli, Xu Hongen, Wang Liang, Tang Wenxue, Chen Bei, Zhao Xingle
Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
Precision Medicine Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
Mol Ther Methods Clin Dev. 2025 Jul 21;33(3):101539. doi: 10.1016/j.omtm.2025.101539. eCollection 2025 Sep 11.
Genetic hearing loss, caused by mutations in critical auditory genes, has seen promising advances through gene therapy, yet the temporal dynamics of early-stage auditory functional recovery and therapeutic transgene expression patterns following intervention remain uncharacterized in preclinical deafness models. This study systematically investigates the post-treatment progression of cochlear functional restoration and spatially resolved transgene expression kinetics in adult knockout ( ) mice following adeno-associated virus (AAV)-mediated inner ear gene therapy. AAV8 vectors delivering were injected via the posterior semicircular canal (PSCC), with auditory brainstem response (ABR) thresholds and cochlear transgene expression assessed at days 1-14 post-injection. VGLUT3 expression in mice revealed rapid transduction, detectable in inner hair cells (IHCs) by day 1, peaking at day 14. Remarkably, hearing recovery commenced as early as day 1 post-injection, and plateaued near wild-type (WT) levels by day 5. Functional correlation analysis demonstrated a robust inverse relationship between FLAG expression and hearing thresholds. This study provides critical insights into the dynamic processes underlying cochlear gene therapy and challenges the conventional paradigm that 1-2 weeks are required for functional recovery.
由关键听觉基因的突变引起的遗传性听力损失，通过基因治疗已取得了令人鼓舞的进展，然而在临床前耳聋模型中，干预后早期听觉功能恢复的时间动态以及治疗性转基因表达模式仍未得到表征。本研究系统地调查了成年敲除（ ）小鼠在腺相关病毒（AAV）介导的内耳基因治疗后耳蜗功能恢复的治疗后进展以及空间分辨的转基因表达动力学。通过后半规管（PSCC）注射携带 的AAV8载体，并在注射后第1 - 14天评估听觉脑干反应（ABR）阈值和耳蜗转基因表达。 小鼠中的VGLUT3表达显示出快速转导，在第1天在内毛细胞（IHC）中可检测到，在第14天达到峰值。值得注意的是，听力恢复早在注射后第1天就开始了，并在第5天接近野生型（WT）水平趋于平稳。功能相关性分析表明FLAG表达与听力阈值之间存在强烈的负相关关系。本研究为耳蜗基因治疗的动态过程提供了关键见解，并挑战了功能恢复需要1 - 2周的传统范式。
