Engineered virus-like particles for in vivo gene editing ameliorate hearing loss in murine DFNA2 model.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-09-02 DOI:10.1016/j.ymthe.2025.08.049

Byunghwa Noh,Ramu Gopalappa,Haiyue Lin,Heon Yung Gee,Jae Young Choi,Hyongbum Henry Kim,Jinsei Jung

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引用次数: 0

Abstract

Although gene editing therapy is applicable to human diseases, its efficiency and safety require further investigation. Further, non-virus-mediated gene editor delivery is challenging in the inner ear. Here, engineered virus-like particles (eVLPs) were used for inner-ear delivery of SpCas9 and single-guided RNA to delete the Kcnq4 dominant-negative mutant allele, which causes progressive hearing loss in a non-syndromic hearing loss murine model. eVLP-delivered SpCas9 was administered to the inner ears of Kcnq4W277S/+ mice to target the Kcnq4-expressing outer hair cells (OHCs). Hearing loss was significantly alleviated 7 weeks after eVLP administration. OHC survival improved significantly, and OHC-innervating neurite (connected to type II spiral ganglion neuronal body) loss was ameliorated. Finally, OHC membrane potential was hyperpolarized with eVLP gene editor treatment in Kcnq4-mutant mice, indicating that their OHCs were healthier and more stable than those of uninjected mice. Our findings suggest that eVLPs are feasible inner ear gene editor deliverers to treat hearing loss.

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用于体内基因编辑的工程病毒样颗粒改善了小鼠DFNA2模型的听力损失。

虽然基因编辑疗法适用于人类疾病，但其有效性和安全性有待进一步研究。此外，在内耳中非病毒介导的基因编辑器递送具有挑战性。在这里，使用工程病毒样颗粒（evlp）内耳递送SpCas9和单导RNA来删除Kcnq4显性阴性突变等位基因，该等位基因在非综合征性听力损失小鼠模型中导致进行性听力损失。将evlp传递的SpCas9注入Kcnq4W277S/+小鼠内耳，靶向表达kcnq4的外毛细胞（ohc）。eVLP给药7周后听力损失明显减轻。OHC存活率显著提高，OHC支配的神经突（连接II型螺旋神经节神经元体）丢失得到改善。最后，在kcnq4突变小鼠中，eVLP基因编辑器处理后OHC膜电位超极化，表明其OHC比未注射小鼠更健康，更稳定。我们的研究结果表明，evlp是治疗听力损失的可行内耳基因编辑器递送物。

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

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.