PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-15 DOI:10.1172/JCI177700
Maryna V Ivanchenko, Daniel M Hathaway, Eric M Mulhall, Kevin Ta Booth, Mantian Wang, Cole W Peters, Alex J Klein, Xinlan Chen, Yaqiao Li, Bence György, David P Corey
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Abstract

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

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PCDH15 双 AAV 基因疗法治疗乌谢尔综合征 1F 型模型的失聪和失明。
1F型乌谢尔综合征(USH1F)是由原粘连蛋白-15(PCDH15)基因突变引起的,其特征是先天性听力和平衡感缺失,并以视网膜色素变性的形式进行性失明。在这项研究中,我们探索了一种 USH1F 基因治疗方法,通过采用双重腺相关病毒 (AAV) 策略来传递全长 PCDH15 编码序列,从而突破了单一 AAV 包装的限制。我们在小鼠 USH1F 模型中证明了这一策略的有效性,有效恢复了这些小鼠的听力和平衡能力。重要的是,我们的方法还成功地在临床相关视网膜模型(包括人类视网膜器官组织和非人灵长类视网膜)中表达了 PCDH15 蛋白,显示了光感受器的高效靶向性和萼状过程中蛋白质的正确表达。这项研究标志着我们在推进针对 USH1F 以及听力、平衡和视力损伤等多重挑战的基因疗法方面迈出了重要一步。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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