CRISPR-free RNA base editing mediated PTC-readthrough restores hearing in mice with Otof nonsense mutation

The gene therapy achieved by AAV-mediated otoferlin-overexpression is an effective therapeutic strategy for congenital deafness. However, achieving its physiological and endogenous patterns of expression remains challenging. Here, we generate the homologous mutation Otof c.1315 C > T (p.R439*), equivalent to OTOF c.1273 C > T (p.R425*) found in humans with profound deafness, to create a nonsense mutation-induced deaf mouse model. We then deliver the 'RESTART v3' system, which is a CRISPR-free RNA base editor for nonsense mutation suppression, into the cochlea of the mice. We achieve physiological otoferlin expression, and the edited premature termination codon is reverse-mutated to the original amino acid. We observe significant hearing restoration and enhancement of the behavioral auditory startle reflex. Thus, our study presents a successful RNA editing strategy to significantly restore hereditary deafness in mice carrying the specific Otof nonsense mutation, which holds great promise for future clinical translation.

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Publication Details

Journal
Nature Communications
Published
2025-12-06
DOI
https://doi.org/10.1038/s41467-025-67112-w
Primary Topic
RNA regulation and disease
Type
article
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article

CRISPR-free RNA base editing mediated PTC-readthrough restores hearing in mice with Otof nonsense mutation

Chengqi Yi, Jinghui Song, Qianru Yu, Qiang Huang et al.
Nature Communications
RNA regulation and disease
article

CRISPR-free RNA base editing mediated PTC-readthrough restores hearing in mice with Otof nonsense mutation

Chengqi Yi, Jinghui Song, Qianru Yu, Qiang Huang, Nan Luo, Shusheng Gong, Meng-Hua Li, Wei Xiong, Ke Liu, Wenqing Liu, Teng Qi, Hanxiao Sun, Xi Shi, Rui Guo, Yang Li
article en

Abstract

The gene therapy achieved by AAV-mediated otoferlin-overexpression is an effective therapeutic strategy for congenital deafness. However, achieving its physiological and endogenous patterns of expression remains challenging. Here, we generate the homologous mutation Otof c.1315 C > T (p.R439*), equivalent to OTOF c.1273 C > T (p.R425*) found in humans with profound deafness, to create a nonsense mutation-induced deaf mouse model. We then deliver the 'RESTART v3' system, which is a CRISPR-free RNA base editor for nonsense mutation suppression, into the cochlea of the mice. We achieve physiological otoferlin expression, and the edited premature termination codon is reverse-mutated to the original amino acid. We observe significant hearing restoration and enhancement of the behavioral auditory startle reflex. Thus, our study presents a successful RNA editing strategy to significantly restore hereditary deafness in mice carrying the specific Otof nonsense mutation, which holds great promise for future clinical translation.

Nature CommunicationsVol. 17(1)
Capital Medical University (CN), Peking University (CN), Hainan University (CN), Bruker (China) (CN), Beijing Friendship Hospital (CN), Center for Life Sciences (CN), Tsinghua University (CN)
Openalex Percentile: Top 65%
RNA regulation and disease
DOIOpen Access PDFOpenAlex
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