遗传性耳聋的新兴疗法：精准基因编辑的兴起

文献信息

中文摘要

背景： 听力损失是一种普遍的感觉障碍，具有深远的社会和健康影响。尽管助听器和人工耳蜗可以显著恢复听觉感知，但它们无法解决潜在的遗传病因。遗传性听力损失通常为单基因遗传，是基因治疗的理想候选对象，尤其是已有超过150个基因与耳聋相关。载体工程和基因组编辑技术的进步使得能够精准靶向内耳中的听觉细胞。成簇规律间隔短回文重复序列-Cas系统、碱基编辑和先导编辑等技术为在天然基因组位点纠正致病性变异提供了强大工具。本综述总结了针对遗传性和获得性听力损失的基因编辑方法的最新进展，重点介绍了涵盖显性和隐性耳聋形式的小鼠模型中的关键临床前研究。我们讨论了不同编辑技术、载体递送系统和给药途径的优势与局限性，并探讨了编辑效率、细胞特异性靶向以及这些疗法向人类转化等障碍。总体而言，这些进展代表了朝着变异特异性、持久且可能治愈的听力损失治疗迈出的关键一步。

英文摘要

Hearing loss is a prevalent sensory disorder with profound social and health impacts. Although hearing aids and cochlear implants can significantly restore auditory perception, they do not address the underlying genetic causes. Inherited forms of hearing loss, often monogenic, are ideal candidates for gene therapy, particularly since over 150 genes have been linked to deafness. Advances in vector engineering and genome editing technologies now enable precise targeting of auditory cells within the inner ear. Technologies such as Clustered Regularly Interspaced Short Palindromic Repeats-Cas systems, base editing, and prime editing offer powerful tools to correct pathogenic variants at their native genomic loci. This review summarizes the current landscape of gene editing approaches for both hereditary and acquired hearing loss, emphasizing key preclinical studies in mouse models encompassing dominant and recessive forms of deafness. We discuss the advantages and limitations of different editing techniques, vector delivery systems, and administration routes, and explore obstacles including editing efficiency, cell-specific targeting, and the translation of these therapies to humans. Collectively, these advances represent a pivotal step toward variant-specific, durable, and potentially curative treatments for hearing loss.