Vona Barbara, Wollnik Bernd, Strenzke Nicola, Pangršič Tina, Moser Tobias
Institute of Human Genetics University Medical Center Göttingen Göttingen Germany.
Institute for Auditory Neuroscience and InnerEarLab University Medical Center Göttingen Göttingen Germany.
MedComm (2020). 2025 Sep 8;6(9):e70363. doi: 10.1002/mco2.70363. eCollection 2025 Sep.
modulates presynaptic Ca1.3 Ca channel function in inner hair cells (IHCs) and is required for indefatigable synaptic sound encoding. Biallelic variants in are associated with non-syndromic hearing loss (DFNB93). Otoacoustic emissions have been observed in an Italian family with a homozygous variant, indicating preservation of outer hair cell-mediated cochlear amplification. Hence, DFNB93 belongs to the hearing disorders caused by impairment of IHC synapses, termed auditory synaptopathy. DFNB93 mouse models have recapitulated findings and demonstrated that lack of CaBP2 impairs synaptic sound encoding by enhanced steady-state inactivation of Ca1.3 Ca channels. Furthermore, preclinical studies have demonstrated feasibility of gene therapy. As growing evidence from clinical trials confirms synaptopathies as promising therapeutic targets for hearing restoration, ranks highly among the candidate genes for virus-mediated gene therapy to restore hearing. This perspective summarizes the preclinical gene replacement studies for hereditary hearing loss and outlines the characteristics that make genetic targets ideal for therapy development. It reviews the current literature on human studies, pre-clinical therapy development, and introduces a patient registry that aims to support research involvement with the patient community. We conclude with a preview of the next steps toward gene therapy clinical trials.
调节内毛细胞（IHC）中的突触前Ca1.3钙通道功能，是不间断的突触声音编码所必需的。该基因的双等位基因变异与非综合征性听力损失（DFNB93）相关。在一个具有纯合该变异的意大利家族中观察到了耳声发射，表明外毛细胞介导的耳蜗放大功能得以保留。因此，DFNB93属于由IHC突触损伤引起的听力障碍，称为听觉突触病。DFNB93小鼠模型重现了相关发现，并证明缺乏CaBP2会通过增强Ca1.3钙通道的稳态失活来损害突触声音编码。此外，临床前研究已经证明了基因治疗的可行性。随着越来越多来自临床试验的证据证实突触病是听力恢复的有前景的治疗靶点，该基因在病毒介导的恢复听力的基因治疗候选基因中排名很高。这篇综述总结了遗传性听力损失的临床前基因替代研究，并概述了使基因靶点成为治疗开发理想选择的特征。它回顾了当前关于人类该基因研究、临床前治疗开发的文献，并介绍了一个旨在支持患者群体参与研究的患者登记处。我们最后预览了该基因治疗临床试验的下一步计划。
