Optimized in vivo base editing restores auditory function in a DFNA15 mouse model
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 Pou4f3<sup>WT/Q113*</sup> mutant mouse model mimicking DFNA15. We develop and screen adenine base editors (ABEs) targeting the Pou4f3<sup>Q113*</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 Pou4f3<sup>WT/Q113*</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.
Authors
- Jieyu Qi (ORCID: https://orcid.org/0000-0001-8780-0710)
- Fangzhi Tan (ORCID: https://orcid.org/0000-0002-8230-1784)
- Nianci Li
- Renjie Chai (ORCID: https://orcid.org/0000-0002-3885-543X)
- Zuhong He (ORCID: https://orcid.org/0000-0001-6409-4366)
- Qiuhan Sun
- Man Wang (ORCID: https://orcid.org/0000-0002-3636-2789)
- Xiaohan Wang (ORCID: https://orcid.org/0000-0001-8493-8773)
- Liyan Zhang (ORCID: https://orcid.org/0000-0003-4582-2414)
- Ziyu Zhang (ORCID: https://orcid.org/0000-0002-9774-4879)
- Xiangyan Chen (ORCID: https://orcid.org/0000-0003-2002-0327)
- Hongbo Yang (ORCID: https://orcid.org/0009-0004-2525-9462)
- Yicheng Lu
Institutions
- Beijing Institute of Technology (CN)
- University of Electronic Science and Technology of China (CN)
- Nantong University (CN)
- Beijing Electronic Science and Technology Institute (CN)
- Wuhan University (CN)
- Southeast University (BD)
- Zhongda Hospital Southeast University (CN)
- Jinan Institute of Quantum Technology (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Southeast University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-18
- DOI
- https://doi.org/10.1038/s41467-025-63613-w
- Citations
- 2
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Southeast University
- National Key Research and Development Program of China