{"title":"Deciphering enhancers of hearing loss genes for efficient and targeted gene therapy of hereditary deafness.","authors":"Simeng Zhao, Qiuxiang Yang, Zehua Yu, Cenfeng Chu, Shengqi Dai, Hongli Li, Min Diao, Lingyue Feng, Junzi Ke, Yilin Xue, Qifang Zhou, Yan Liu, Hanhui Ma, Chao-Po Lin, Yong-Gang Yao, Guisheng Zhong","doi":"10.1016/j.neuron.2025.03.023","DOIUrl":null,"url":null,"abstract":"<p><p>Hereditary hearing loss accounts for about 60% of congenital deafness. Although adeno-associated virus (AAV)-mediated gene therapy shows substantial potential for treating genetic hearing impairments, there remain significant concerns regarding the specificity and safety of AAV vectors. The sophisticated nature of the cochlea further complicates the challenge of precisely targeting gene delivery. Here, we introduced an AAV-reporter-based in vivo transcriptional enhancer reconstruction (ARBITER) workflow, enabling efficient and reliable dissection of enhancers. With ARBITER, we successfully demonstrated that the conserved non-coding elements (CNEs) within the gene locus collaboratively regulate the expression of Slc26a5, which was further validated using knockout mouse models. We also assessed the potential of identified enhancers to treat hereditary hearing loss by conducting gene therapy in Slc26a5 mutant mice. Based on the original Slc26a5 enhancer with limited efficiency, we engineered a highly efficient and outer hair cell (OHC)-specific enhancer, B8, which successfully restored hearing of Slc26a5 knockout mice.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1579-1596.e5"},"PeriodicalIF":14.7000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuron","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuron.2025.03.023","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Hereditary hearing loss accounts for about 60% of congenital deafness. Although adeno-associated virus (AAV)-mediated gene therapy shows substantial potential for treating genetic hearing impairments, there remain significant concerns regarding the specificity and safety of AAV vectors. The sophisticated nature of the cochlea further complicates the challenge of precisely targeting gene delivery. Here, we introduced an AAV-reporter-based in vivo transcriptional enhancer reconstruction (ARBITER) workflow, enabling efficient and reliable dissection of enhancers. With ARBITER, we successfully demonstrated that the conserved non-coding elements (CNEs) within the gene locus collaboratively regulate the expression of Slc26a5, which was further validated using knockout mouse models. We also assessed the potential of identified enhancers to treat hereditary hearing loss by conducting gene therapy in Slc26a5 mutant mice. Based on the original Slc26a5 enhancer with limited efficiency, we engineered a highly efficient and outer hair cell (OHC)-specific enhancer, B8, which successfully restored hearing of Slc26a5 knockout mice.
期刊介绍:
Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.