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<p>Genetic mutations cause hereditary deafness, in which mutations in the POU4 transcription factor 3 gene (<i>POU4F3</i>) lead to autosomal dominant non-syndromic deafness 15 (DFNA15), for which no effective clinical treatment currently exists. Gene editing holds promise for precisely repairing mutated nucleotides, thus offering a potential cure for hereditary hearing loss. Here, we establish a <i>Pou4f3</i><sup><i>WT/Q113*</i></sup> mutant mouse model mimicking DFNA15. We develop and screen adenine base editors (ABEs) targeting the <i>Pou4f3</i><sup><i>Q113*</i></sup> allele by fusing diverse adenine deaminases to Cas9 we discovered before. SchABE8e accomplishes highly precise and efficient editing (up to 48.5%) at sgRNA3 in vitro. Neonatal <i>Pou4f3</i><sup><i>WT/Q113*</i></sup> mice are treated via synthetic AAV (Anc80L65)-delivered SchABE8e-sgRNA3, resulting in near-complete hearing recovery, with the effect persisting for at least four months. Biosafety analyses further support the feasibility of base editing, providing a therapeutic strategy for DFNA15.</p>

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Optimized in vivo base editing restores auditory function in a DFNA15 mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月18日

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  • Man Wang,
  • Ziyu Zhang,
  • Xiaohan Wang,
  • Liyan Zhang,
  • Xiangyan Chen,
  • Nianci Li,
  • Qiuhan Sun,
  • Yicheng Lu,
  • Zuhong He,
  • Hongbo Yang,
  • Fangzhi Tan,
  • Jieyu Qi,
  • Renjie Chai

摘要

Genetic mutations cause hereditary deafness, in which mutations in the POU4 transcription factor 3 gene (POU4F3) lead to autosomal dominant non-syndromic deafness 15 (DFNA15), for which no effective clinical treatment currently exists. Gene editing holds promise for precisely repairing mutated nucleotides, thus offering a potential cure for hereditary hearing loss. Here, we establish a Pou4f3WT/Q113* mutant mouse model mimicking DFNA15. We develop and screen adenine base editors (ABEs) targeting the Pou4f3Q113* allele by fusing diverse adenine deaminases to Cas9 we discovered before. SchABE8e accomplishes highly precise and efficient editing (up to 48.5%) at sgRNA3 in vitro. Neonatal Pou4f3WT/Q113* mice are treated via synthetic AAV (Anc80L65)-delivered SchABE8e-sgRNA3, resulting in near-complete hearing recovery, with the effect persisting for at least four months. Biosafety analyses further support the feasibility of base editing, providing a therapeutic strategy for DFNA15.