ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Otorhinolaryngology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
Am J Hum Genet. 2024 Oct 3;111(10):2253-2264. doi: 10.1016/j.ajhg.2024.08.008. Epub 2024 Sep 5.
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.
基因治疗在遗传性听力损失的治疗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与耳聋相关的基因上，而对多部位表达的耳聋基因关注较少。MPZL2 是导致轻度至中度遗传性耳聋的第二大原因，广泛表达于不同内耳细胞中。我们构建了一个 Mpzl2 基因缺失的小鼠模型，该模型表现出中度且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 介导的基因替换治疗系统，可在各种耳蜗细胞中进行高效转导。AAV-ie-Mpzl2 给药至少七个月后，可显著降低 Mpzl2 小鼠的听觉脑干反应和畸变产物耳声发射阈值。AAV-ie-Mpzl2 传递可恢复外毛细胞和 Deiters 细胞的结构完整性。本研究提示了基因治疗在 MPZL2 相关耳聋中的应用潜力，并为针对在耳蜗内不同细胞群体中表达的其他耳聋相关基因的基因治疗提供了概念验证。
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