A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness.

OTOF基因内普遍存在的隐性突变（c.2485C>T，p.Q829X）会导致严重的语前听力损失。在这里，我们发现，在携带与人类OTOF纯合的突变 (c.2482C>T, p.Q828X) 的Otof小鼠中，该突变忠实地模拟了听力损失表型，其中有一个碱基编辑器（由脱氨酶 ABE7.10max 和 Cas9 变体 SpCas9 组成） -NG）包装在腺相关病毒中并通过圆窗膜注射到小鼠内耳中，有效纠正了致病突变，没有明显的脱靶效应。该治疗恢复了 88% 内毛细胞中的 otoferlin 蛋白水平，并在超过 1.5 年的时间里将小鼠的听觉功能稳定地恢复到接近野生型水平，同时改善了内毛细胞的突触胞吐作用。我们还表明，针对普遍的人类OTOF突变的腺嘌呤碱基编辑器将人源化小鼠的听力恢复到与野生型小鼠相当的水平。碱基编辑可能对治疗遗传性耳聋有效。