耳畸蛋白基因治疗：耳与听力特刊——听力损失基因治疗叙述性综述

文献信息

中文摘要

在过去十年中，基因治疗在治疗许多遗传性疾病方面显示出前景。遗传性听力障碍是下一个有希望的前沿领域之一。许多早期开发工作集中在由耳畸蛋白基因（OTOF）突变引起的听力障碍上，因为这些突变在保留的听觉外毛细胞存在的情况下导致深度耳聋，而这些细胞在出生后通常可保留多年。动物模型显示，基因递送的靶细胞——内毛细胞——也存在且存活，并且它们位于结构完整且在其他方面功能正常的器官中。最近报道的OTOF基因治疗取得的显著成功，作为概念验证，表明基因治疗可以有效且安全地改善这种以及可能其他形式的遗传性耳聋的听力。在此，作者综述了耳畸蛋白及其在听力中的作用、OTOF致病性变异在听力损失中的作用、该疾病的自然史，以及OTOF基因治疗的临床前研究和当前人体临床试验的结果。

英文摘要

In the last decade, gene therapy has shown promise in treating many genetic disorders. Hereditary hearing impairment represents one of the next promising frontiers. Many initial development efforts have focused on hearing impairment caused by mutations in the otoferlin gene (OTOF), as these mutations cause profound deafness in the setting of preserved auditory outer hair cells, which often remain for many years after birth. Animal models have shown that the target cells for gene delivery, the inner hair cells, are also present and viable, and they reside in a structurally intact organ that is otherwise functional. Recent remarkable successes reported with OTOF gene therapy serve as proof of concept that gene therapy can effectively and safely improve hearing for this and likely other forms of genetic deafness. Here, the authors review the otoferlin protein and its role in hearing, the role of pathogenic variants in OTOF in hearing loss, the natural history of the condition, and the results of preclinical studies and of current human clinical trials of OTOF gene therapy.