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<p>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 <i>Otof c.1315 C</i> &gt; <i>T</i> (p.R439*), equivalent to <i>OTOF c.1273 C</i> &gt; <i>T</i> (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 <i>Otof</i> nonsense mutation, which holds great promise for future clinical translation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月6日

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

摘要

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.