复旦大学舒易来小组近日取得一项新成果。经过不懈努力，他们探明了OTOF相关性耳聋的多中心基因治疗随访2.5年。相关论文于2026年4月22日发表在《自然》杂志上。

常染色体隐性耳聋以OTOF基因突变为主导，以重度至完全性先天性耳聋为特征。尽管基因治疗在少数患者中显示出益处，但其在更广泛的年龄范围和更长的随访期内的安全性和有效性，以及治疗结果的预测因素仍不清楚。在这项在8个中心进行的单臂、多中心试验中，42名参与者（年龄0.8-32.3岁）， 在三个载体剂量组中接受了携带人类OTOF编码转基因（AAV1-hOTOF）的血清型1型腺相关病毒（AAV），随访时间长达2.5年。主要终点为6周内的剂量限制性毒性。次要终点评估疗效和不良事件。未观察到剂量限制性毒性。3级不良事件包括中性粒细胞计数减少。

在接受AAV1-hOTOF治疗的参与者中，90%的人听力恢复，听觉脑干反应阈值从基线时 >97±1 dB正常听力级，逐渐且稳定地改善，在1年、1.5年、2年和2.5年时分别降至54±3、51±3、50±3和42±5 dB正常听力级；行为测听阈值从基线时 >96±3 dB听力级改善至2.5年时的37±5 dB听力级。参与者年龄在0.5-18岁之间老年人的听力改善程度高于成年人。在基线或双等位基因非截断的OTOF变体中，较高数量的当前失真产物耳声发射与更好的听力恢复有关。听力恢复的参与者表现出语言感知的逐渐改善。AAV1-hOTOF在更广泛的患者群体中具有良好的耐受性和有效性，持续治疗效果长达2.5年。中国临床试验注册中心注册号：ChiCTR2200063181。

附：英文原文

Title: Multicentre gene therapy for OTOF-related deafness followed up to 2.5 years

Author: Jiang, Luoying, Cheng, Xiaoting, Lv, Jun, Chen, Yuxin, Chen, Xiaoyun, Zhai, Rongqun, Zhang, Liqin, Han, Lei, Zhang, Yiling, Zhang, Juhong, Deng, Di, Huang, Zhicheng, Cao, Qi, Zhang, Xin, Wang, Daqi, Wang, Yizhe, Chen, Liheng, Yu, Sha, Guo, Luo, Zhang, Bowen, Wang, Hui, Zhou, Yi, Dai, Liling, Wang, Wei, Zhang, Longlong, Yin, Yanbo, Cheng, Guiqing, Zhou, Ziyi, Wang, Wuqing, Chen, Bing, Lu, Wei, Jiang, Hongqun, Gao, Zhiqiang, Shi, Dazhi, Xiong, Yuanping, Zhao, Yu, Yuan, Wei, Wang, Qin, Feng, Guodong, Li, Huawei, Chen, Zheng-Yi, Shu, Yilai

Issue&Volume: 2026-04-22

Abstract: Autosomal recessive deafness 9, caused by OTOF gene mutations, is characterized by severe-to-complete congenital deafness1. Although gene therapy has shown benefits in a small number of patients2,3,4,5, its safety and efficacy across broader age ranges and longer follow-up periods, as well as predictors of treatment outcomes, remain unclear. In this single-arm, multicentre trial conducted at eight centres, 42 participants (aged 0.8–32.3years) received adeno-associated virus (AAV) serotype 1 carrying a human OTOF coding transgene (AAV1-hOTOF) at three vector dose groups, with up to 2.5-year follow-up. The primary end point was dose-limiting toxicity within 6weeks. The secondary end point assessed efficacy and adverse events. No dose-limiting toxicities were observed. Grade 3 adverse events included decreased neutrophil count. Hearing was recovered in 90% of participants treated with AAV1-hOTOF, with gradual and stable improvement in auditory brainstem response threshold from greater than 97±1dB normalized hearing level at baseline to 54±3, 51±3, 50±3 and 42±5dB normalized hearing level at 1, 1.5, 2 and 2.5years, respectively, and behavioural audiometry improving from greater than 96±3dB hearing level at baseline to 37±5dB hearing level at 2.5years. Participants aged 0.5–18years showed greater hearing improvement than adults. A higher number of present distortion product otoacoustic emissions at baseline or biallelic non-truncated OTOF variants was associated with better hearing recovery. Participants with hearing recovery demonstrated gradual improvement in speech perception. AAV1-hOTOF is well-tolerated and efficacious across a broader patient population, with sustained therapeutic benefits for up to 2.5years. Chinese Clinical Trial Registry registration: ChiCTR2200063181.

DOI: 10.1038/s41586-026-10393-y

Source: https://www.nature.com/articles/s41586-026-10393-y