Ivanchenko Maryna V, Hathaway Daniel M, Mulhall Eric M, Booth Kevin T, Wang Mantian, Peters Cole W, Klein Alex J, Chen Xinlan, Li Yaqiao, György Bence, Corey David P
bioRxiv. 2023 Nov 13:2023.11.09.566447. doi: 10.1101/2023.11.09.566447.
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 a novel 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 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.
1F型Usher综合征（USH1F）由原钙黏蛋白-15（PCDH15）基因突变引起，其特征为先天性听力和平衡功能缺失，以及色素性视网膜炎形式的进行性失明。在本研究中，我们探索了一种用于USH1F基因治疗的新方法，通过采用双腺相关病毒（AAV）策略递送全长PCDH15编码序列，突破了单一AAV包装限制。我们在小鼠USH1F模型中证明了该策略的有效性，有效恢复了这些小鼠的听力和平衡。重要的是，我们的方法在临床相关的视网膜模型中也成功表达了PCDH15，包括人类视网膜类器官和非人类灵长类动物视网膜，显示出对光感受器的有效靶向以及在萼状突中的正确蛋白质表达。这项研究代表了在推进USH1F基因治疗以及应对听力、平衡和视力损害等多重挑战方面迈出的重要一步。
