Article record

用于支持OTOF相关耳聋基因治疗临床试验的不确定意义变异分类转化流程

A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness.

基础研究耳科IF 13Q1

文献信息

PMID	42843343
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Liheng Chen 查看其他 25 位作者 Min Yao；Honghai Tang；Jingjing Zhao；Dan Mu；Daqi Wang；Sha Yu；Luo Guo；Qi Cao；Luoying Jiang；Chong Cui；Lei Han；Yuan Yuan；Shuang Han；Sen Zhang；Xiaoyi Gu；Yicheng Zeng；Bowen Zhang；Qi Zhao；Shuyuan Li；Yiyao Chen；Ru Zhang；Huawei Li；Zhaoxin Ma；Geng-Lin Li；Yilai Shu
作者单位	ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China; State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. 查看其他 9 条单位信息 Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China; State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Otolaryngology-Head and Neck Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.；Department of Otolaryngology, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China.；ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China; State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Otolaryngology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.；The Reproduction Hospital of Guangxi Zhuang Autonomous Region, Nanning 530218, China.；International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.；Department of Otorhinolaryngology-Head and Neck Surgery, Huadong Hospital, Fudan University, Shanghai 200233, China.；Department of Otolaryngology-Head and Neck Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: mzhx114@163.com.；ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China; State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: genglin.li@fdeent.org.；ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China; State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Institute of Medical Genetics and Genomics, Fudan University, Shanghai 200032, China; Shanghai Academy of Natural Sciences (SANS), Shanghai 200031, China; FuRong Laboratory, Changsha 410078, China. Electronic address: yilai_shu@fudan.edu.cn.
期刊	Cell reports. Medicine
SCI 分区	Q1
IF	13
研究类型	基础研究 · 基础／转化
所属专科	耳科

中文摘要

背景： OTOF基因功能障碍导致先天性耳聋。OTOF基因治疗已取得有希望的临床疗效。然而，OTOF不确定意义变异（VUS）阻碍了诊断，并限制了在我们队列中135名具有双等位基因OTOF变异的听力损失患者中一半患者的基因治疗资格。方法：在此，我们建立了一个转化流程，通过功能分析重新分类VUS并指导临床决策。我们使用腺相关病毒（AAV）介导的变异递送系统将编码VUS递送到Otof-/-小鼠中，并通过剪接试验评估非编码VUS。结果：分离的纯合E1700Q赋予正常听力，而E1700Q在患者中始终与K1992R顺式出现，且K1992R与异常的otoferlin亚细胞定位相关。该流程重新分类了八个代表性VUS，为38名患者提供了明确的分子诊断。七名符合条件的患者接受了基因治疗并显示出听觉改善，其中一名患者实现了接近正常的听力并持续了1.5年。结论：该流程有效扩大了OTOF相关耳聋的基因治疗资格。本研究已在中国临床试验注册中心注册：ChiCTR2200063181。

英文摘要

OTOF gene dysfunction causes congenital deafness. OTOF gene therapy achieves promising clinical efficacy. However, OTOF variants of uncertain significance (VUS) hinder diagnosis and restrict eligibility for gene therapy in half of 135 hearing loss patients with biallelic OTOF variants in our cohort. Here, we establish a translational pipeline to reclassify VUSs and guide clinical decisions via functional analysis. We evaluate coding VUSs using an adeno-associated virus (AAV)-mediated variant delivery system into Otof-/- mice and evaluate non-coding VUSs via splicing assays. Isolated homozygous E1700Q confers normal hearing, while E1700Q consistently occurs in cis with K1992R in patients, and K1992R correlates with abnormal otoferlin subcellular localization. This pipeline reclassifies eight representative VUSs, enabling definitive molecular diagnoses for 38 patients. Seven eligible patients receive gene therapy and show auditory improvement, including one achieving near-normal hearing that was sustained for 1.5 years. This pipeline effectively expands the gene therapy eligibility for OTOF-related deafness. This study is registered with the Chinese Clinical Trial Registry: ChiCTR2200063181.