Deciphering enhancers of hearing loss genes for efficient and targeted gene therapy of hereditary deafness.

IF 14.7 1区 医学 Q1 NEUROSCIENCES
Neuron Pub Date : 2025-05-21 Epub Date: 2025-04-21 DOI:10.1016/j.neuron.2025.03.023
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
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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.

破解听力损失基因增强子对遗传性耳聋的有效和靶向基因治疗。
遗传性听力损失约占先天性耳聋的60%。尽管腺相关病毒(AAV)介导的基因疗法显示出治疗遗传性听力障碍的巨大潜力,但AAV载体的特异性和安全性仍然值得关注。耳蜗的复杂特性进一步复杂化了精确定位基因传递的挑战。在这里,我们介绍了一种基于aav报告器的体内转录增强子重建(ARBITER)工作流程,能够高效可靠地解剖增强子。通过ARBITER,我们成功地证明了基因座内的保守非编码元件(CNEs)协同调节Slc26a5的表达,并通过敲除小鼠模型进一步验证了这一点。我们还通过对Slc26a5突变小鼠进行基因治疗,评估了鉴定出的增强子治疗遗传性听力损失的潜力。在原Slc26a5增强子效率有限的基础上,我们设计了一种高效的外毛细胞(OHC)特异性增强子B8,成功恢复了Slc26a5敲除小鼠的听力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuron
Neuron 医学-神经科学
CiteScore
24.50
自引率
3.10%
发文量
382
审稿时长
1 months
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.
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