A base editor for the long-term restoration of auditory function in mice with recessive profound deafness

IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Nature Biomedical Engineering Pub Date : 2024-08-12 DOI:10.1038/s41551-024-01235-1
Chong Cui, Shengyi Wang, Daqi Wang, Jingjing Zhao, Bowei Huang, Biyun Zhu, Yuxin Chen, Honghai Tang, Yu Han, Cheng Ye, Dan Mu, Chengdong Zhang, Yuan Yang, Yihan Bao, Jun Lv, Shuang Han, Geng-Lin Li, Huawei Li, Yilai Shu
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Abstract

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.

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隐性极重度耳聋小鼠听觉功能长期恢复的基础编辑器
OTOF 基因中的一个普遍隐性突变(c.2485C>T, p.Q829X)会导致深度舌前听力损失。在这里,我们发现在携带突变(c.2482 C>T, p.Q829XC>T,p.Q828X)的Otof小鼠中,这种基因突变忠实地模拟了听力损失的表型,将碱基编辑器(由脱氨酶ABE7.10max和Cas9变体SpCas9-NG组成)包装在腺相关病毒中,通过圆窗膜注入小鼠内耳,可有效纠正致病突变,且无明显的脱靶效应。治疗恢复了 88% 的内毛细胞的奥托费林蛋白水平,并在 1.5 年多的时间里将小鼠的听觉功能稳定地恢复到接近野生型的水平,同时改善了内毛细胞的突触外泌功能。我们还发现,针对人类普遍存在的OTOF突变的腺嘌呤碱基编辑器能使人源化小鼠的听力恢复到与野生型小鼠相当的水平。碱基编辑器可能对治疗遗传性耳聋有效。
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来源期刊
Nature Biomedical Engineering
Nature Biomedical Engineering Medicine-Medicine (miscellaneous)
CiteScore
45.30
自引率
1.10%
发文量
138
期刊介绍: Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.
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