The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.
The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.
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DOI：
10.1172/jci.insight.148586
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发表时间：
2022-02-08
期刊：
影响因子：
8
通讯作者：
Bitner-Glindzicz M
中科院分区：
文献类型：
--
作者：
Bryant D;Pauzuolyte V;Ingham NJ;Patel A;Pagarkar W;Anderson LA;Smith KE;Moulding DA;Leong YC;Jafree DJ;Long DA;Al-Yassin A;Steel KP;Jagger DJ;Forge A;Berger W;Sowden JC;Bitner-Glindzicz M
诺里病是由NDP基因突变引起的，表现为先天性失明，随后出现听力损失。保护患者免受听力损失对于维持他们的生活质量至关重要。本研究旨在了解耳蜗结构和功能的病理学发病。通过调查患者和青少年Ndp突变小鼠，我们阐明了生理变化（听觉脑干反应，畸变产物耳声发射，耳蜗内电位，血迷路屏障完整性）的发病顺序，并确定了导致听力损失的细胞，组织学和超微结构事件。我们发现，耳蜗血管病变发生早于以前的报告和感音神经性听力损失。这项工作定义了一种疾病机制，即耳蜗微血管的早期畸形先于血管完整性的丧失和耳蜗内电位的下降，导致听力损失和毛细胞死亡，同时保留螺旋神经节细胞。这提供了定义最佳治疗窗口的事件的基本信息，并表明需要早期干预。在基因治疗和小分子技术不断发展的时代，这项研究建立了Ndp突变小鼠作为测试此类干预措施的平台，并对了解诺里病听力损失的进展具有重要意义。
Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.
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