INSERM UMR 1051, Institute for Neurosciences of Montpellier , Montpellier , France ; and University of Montpellier, Montpellier , France.
Physiol Rev. 2018 Oct 1;98(4):2477-2522. doi: 10.1152/physrev.00053.2017.
Sensorineural hearing impairment is the most common sensory disorder and a major health and socio-economic issue in industrialized countries. It is primarily due to the degeneration of mechanosensory hair cells and spiral ganglion neurons in the cochlea via complex pathophysiological mechanisms. These occur following acute and/or chronic exposure to harmful extrinsic (e.g., ototoxic drugs, noise...) and intrinsic (e.g., aging, genetic) causative factors. No clinical therapies currently exist to rescue the dying sensorineural cells or regenerate these cells once lost. Recent studies have, however, provided renewed hope, with insights into the therapeutic targets allowing the prevention and treatment of ototoxic drug- and noise-induced, age-related hearing loss as well as cochlear cell degeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes are showing promise, as are cell-replacement therapies to repair damaged cells for the future restoration of hearing in deaf people. This review begins by recapitulating our current understanding of the molecular pathways that underlie cochlear sensorineural damage, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. It then guides the reader through to the recent discoveries in pharmacological, gene and cell therapy research towards hearing protection and restoration as well as their potential clinical application.
感音神经性听力损失是最常见的感觉障碍，也是工业化国家的主要健康和社会经济问题。它主要是由于耳蜗中的机械感觉毛细胞和螺旋神经节神经元通过复杂的病理生理机制退化所致。这些情况发生在急性和/或慢性暴露于有害的外在（例如，耳毒性药物、噪声等）和内在（例如，衰老、遗传）致病因素之后。目前尚无临床疗法可挽救垂死的感觉神经元细胞，也无法在这些细胞丢失后再生。然而，最近的研究提供了新的希望，深入了解治疗靶点可以预防和治疗耳毒性药物和噪声引起的、与年龄相关的听力损失以及耳蜗细胞退化。此外，涉及替换或纠正突变序列或缺陷基因的遗传途径以及用于修复受损细胞的细胞替代疗法，都为未来聋人听力恢复带来了希望。本综述首先概述了我们目前对耳蜗感觉神经损伤的分子途径以及生存信号通路的理解，这些通路可以提供内源性保护和组织挽救。然后，它引导读者了解药理学、基因和细胞治疗研究中的最新发现，这些研究旨在保护和恢复听力，以及它们的潜在临床应用。
