Wang Man, Zhang Ziyu, Wang Xiaohan, Zhang Liyan, Chen Xiangyan, Li Nianci, Sun Qiuhan, Lu Yicheng, He Zuhong, Yang Hongbo, Tan Fangzhi, Qi Jieyu, Chai Renjie
Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, State Key Laboratory of Digital Medical Engineering, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China.
Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Nat Commun. 2025 Sep 18;16(1):8322. doi: 10.1038/s41467-025-63613-w.
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 mutant mouse model mimicking DFNA15. We develop and screen adenine base editors (ABEs) targeting the Pou4f3 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 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.
基因突变会导致遗传性耳聋，其中POU4转录因子3基因（POU4F3）的突变会导致常染色体显性非综合征性耳聋15型（DFNA15），目前尚无有效的临床治疗方法。基因编辑有望精确修复突变的核苷酸，从而为遗传性听力损失提供潜在的治疗方法。在此，我们建立了一个模拟DFNA15的Pou4f3突变小鼠模型。我们通过将不同的腺嘌呤脱氨酶与之前发现的Cas9融合，开发并筛选了靶向Pou4f3等位基因的腺嘌呤碱基编辑器（ABE）。SchABE8e在体外sgRNA3处实现了高度精确和高效的编辑（高达48.5%）。通过合成腺相关病毒（Anc80L65）递送SchABE8e-sgRNA3对新生Pou4f3小鼠进行治疗，导致听力几乎完全恢复，且效果持续至少四个月。生物安全性分析进一步支持了碱基编辑的可行性，为DFNA15提供了一种治疗策略。
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