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

Author

Listed:
  • Man Wang

    (Southeast University
    Nantong University)

  • Ziyu Zhang

    (Southeast University)

  • Xiaohan Wang

    (Southeast University)

  • Liyan Zhang

    (Southeast University)

  • Xiangyan Chen

    (Southeast University)

  • Nianci Li

    (Southeast University)

  • Qiuhan Sun

    (Southeast University)

  • Yicheng Lu

    (Southeast University)

  • Zuhong He

    (Southeast University
    Zhongnan Hospital of Wuhan University)

  • Hongbo Yang

    (Fudan University)

  • Fangzhi Tan

    (Southeast University)

  • Jieyu Qi

    (Beijing Institute of Technology
    Beijing Institute of Technology
    Beijing Institute of Technology)

  • Renjie Chai

    (Southeast University
    Nantong University
    Beijing Institute of Technology
    University of Electronic Science and Technology of China)

Abstract

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.

Suggested Citation

  • 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, 2025. "Optimized in vivo base editing restores auditory function in a DFNA15 mouse model," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63613-w
    DOI: 10.1038/s41467-025-63613-w
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