Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2−/− mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.

中文翻译：

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通过基因替代疗法恢复人类耳聋小鼠模型中多位点表达基因的听力DFNB111


基因治疗在治疗遗传性听力损失方面取得了重大进展。然而，大多数研究都集中在主要在毛细胞中表达的耳聋相关基因上，而对多位点表达的耳聋基因的关注较少。MPZL2 是轻度至中度遗传性耳聋的第二大原因，在不同的内耳细胞中广泛表达。我们生成了一个 Mpzl2 基因缺失的小鼠模型，该模型显示中度和缓慢进行性听力损失，模拟了 DFNB111 个体的表型。我们开发了一种由 AAV-ie 介导的基因替代疗法系统，用于在各种类型的耳蜗细胞中进行高效转导。AAV-ie-Mpzl2 给药显着降低了 Mpzl2 - / - 小鼠的听觉脑干反应和失真产物耳声发射阈值至少七个月。AAV-ie-Mpzl2 递送恢复了外毛细胞和 Deiters 细胞的结构完整性。这项研究表明基因治疗 MPZL2 相关耳聋的潜力，并为针对在耳蜗不同细胞群中表达的其他耳聋相关基因的基因治疗提供了概念验证。