Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin
Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin
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DOI：
10.1007/s00439-022-02504-2
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发表时间：
2022-11-16
期刊：
影响因子：
5.3
通讯作者：
Shu, Yilai
中科院分区：
文献类型：
--
作者：
Tang, Honghai;Wang, Hui;Shu, Yilai
OTOF基因突变是听神经病变最常见的原因之一。虽然人工耳蜗在恢复声音传导方面通常是有效的，但目前还没有针对OTOF变异个体的生物治疗方法。先前的研究报道了使用OTOF基因替代DFNB9小鼠的听力，但效果有待改进。在这里，我们开发了一种基于蛋白质反式剪接原理的新型双aav介导的基因治疗系统，我们发现该系统可以在单次单侧注射后逆转oof（-/-）小鼠的双侧耳聋。该系统在出生后0-2天注射后有效表达外源性小鼠或人otoferlin。人otoferlin将听力恢复到接近野生型水平至少6个月，并恢复内毛细胞突触囊泡的释放。我们的研究不仅为耳部相关听神经病变的临床治疗提供了优先策略，也为其他大基因治疗和蛋白工程技术的发展提供了一条途径。
Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof(-/-) mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0-2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF-related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.