基因治疗：内耳递送途径

文献信息

中文摘要

基因递送以及用于递送病毒载体的各种给药途径是一个快速发展的领域，近期在正在进行的耳畸蛋白临床试验中，成功恢复了携带OTOF变异儿童患者的听力。随着针对主要遗传性听力障碍（包括综合征型和非综合征型）的基因治疗的兴起，新的递送方法的开发也取得了同步进展。鼓室内注射抗生素和皮质类固醇的进展，加上近半个世纪的耳蜗植入手术经验，使得多种局部和全身方法能够进入内耳。近期工业界对基因治疗和递送技术的投资加速了科学进展，凸显了持续评估针对不同听力损失原因的最合适基因递送策略的必要性。尽管在动物模型中，大多数基因递送是通过圆窗膜注射进行的，在耳蜗毛细胞转导方面产生了有希望的结果，但临床转化仍存在潜在缺点——特别是载体分布有限，可能导致从基底到顶端的梯度。已经探索了诸如镫骨足板开窗或耳道造口术等通气操作来减轻这些限制，并且最近研究了鞘内甚至宫内注射作为替代方法。听力损失可以以多种方式遗传，随着基于CRISPR/Cas的编辑工具最近的成功，患者的基因递送治疗，甚至基因治疗本身的类型，可能会有所不同。了解内耳疾病的遗传病因有助于识别治疗靶点和创新递送方法。本综述总结了目前对基因治疗递送途径的理解，强调了迄今为止在转化和临床研究中展示的各自优势和局限性。此外，它在新兴疗法的背景下探讨了药物递送和临床应用的进展，提供了对基因递送策略未来方向的综合概述和展望。

英文摘要

Gene delivery and the various routes of administration used to deliver viral vectors constitute a rapidly evolving field, with recent success in restoring hearing in children with OTOF variants in ongoing clinical otoferlin trials. With the rise of gene therapy for major hereditary hearing disorders, both syndromic and nonsyndromic, there has been parallel progress in the development of new delivery methods. Advances in intratympanic injection of antibiotics and corticosteroids, along with nearly half a century of experience in cochlear implantation surgery, have enabled multiple local and systemic approaches to access the inner ear. Recent industry investment in gene therapy and delivery technologies has accelerated scientific progress, underscoring the need for continuous evaluation of the most suitable gene delivery strategies for different causes of hearing loss. Although most gene delivery in animal models has been performed via round window membrane injection, yielding promising results in cochlear hair cell transduction, potential drawbacks remain for clinical translation-particularly limited vector distribution, which may result in a basal-to-apical gradient. Venting procedures such as stapes footplate fenestration or canalostomy have been explored to mitigate these limitations, and recent intrathecal or even in utero injections have been investigated as alternative approaches. Hearing loss can be inherited in multiple ways, and patient treatment with gene delivery, or even the type of gene therapy itself, may vary with the recent success of CRISPR/Cas-based editing tools. Understanding the genetic etiology of inner ear disorders has facilitated the identification of therapeutic targets and innovative delivery approaches. This review summarizes the current understanding of delivery routes for gene therapy, highlighting their respective strengths and limitations as demonstrated in translational and clinical research to date. Furthermore, it examines advances in drug delivery and clinical applications in the context of emerging therapeutics, providing an integrated overview and perspective on the future direction of gene delivery strategies.