Ivanchenko Maryna V, Hathaway Daniel M, Mulhall Eric M, Booth Kevin Ta, Wang Mantian, Peters Cole W, Klein Alex J, Chen Xinlan, Li Yaqiao, György Bence, Corey David P
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
J Clin Invest. 2024 Oct 23;134(23):e177700. doi: 10.1172/JCI177700.
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 (dual-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 nonhuman 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USH1F基因治疗方法，通过采用双腺相关病毒（dual-AAV）策略递送全长PCDH15编码序列，突破了单一腺相关病毒包装限制。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功能。重要的是，我们的方法在临床相关视网膜模型中也成功表达了PCDH15蛋白，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杯状突中的正确蛋白表达。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。
