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
{"title":"PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models.","authors":"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","doi":"10.1172/JCI177700","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3000,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/JCI177700","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

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.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
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.
期刊最新文献
Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation-induced surfactant secretion. Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease. Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome. An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety. G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1