Correction of Hearing and Vestibular Defects in a Mouse Model for Deafness

描述（由申请人提供）：这项工作的长期目标是开发先天性耳聋、前庭功能障碍和Usher综合征视网膜色素变性的根治性治疗方法，Usher综合征是导致耳聋和失明的主要遗传原因。这种治疗方法最终可能发展成为一种治疗听力、平衡和视力丧失的方法。在本项目中，我们研究了反义寡核苷酸（ASOs）对小鼠Usher综合征的治疗作用。我们设计了一种ASO来纠正由USH1C基因突变引起的RNA剪接缺陷，这种突变导致小鼠和人类的Usher综合征。初步结果表明，ush1c靶向ASO可恢复小鼠的听力和前庭功能。本项目的目标是进一步发展这种以aso为靶点的方法：1)开发一种基于aso的治疗方案，用于预防/治疗小鼠耳聋和失明；2)评估ush1c靶向ASOs的细胞效应，建立可测量的治疗疗效结局；3)将ASOs局部递送至小鼠耳蜗，提高靶向效果。这些目标的总体目标是将这种aso靶向方法转化为一种治疗方案，为未来的临床试验奠定基础。这项研究的一个深远贡献是证明了ASOs可以有效和有力地靶向耳蜗来拯救听力，这一发现倡导ASOs作为治疗耳部疾病的有前途的工具。

DESCRIPTION (provided by applicant): The long-term goal of this work is to develop a curative treatment for congenital deafness, vestibular dysfunction and retinitis pigmentosa in Usher syndrome, the leading genetic cause of combined deafness and blindness. This treatment approach could ultimately be developed as a therapeutic for hearing, balance and vision loss in general. In this project, we investigate the use of antisense oligonucleotides (ASOs) for the treatment of Usher syndrome in mice. We designed an ASO to correct an RNA splicing defect caused by a mutation in the USH1C gene that causes Usher syndrome in mice and humans. Preliminary results show that an USH1C-targeted ASO rescues hearing and vestibular function in mice. The aims of this project are to further develop this ASO-targeting approach by 1) Developing an ASO-based treatment regimen for the prevention/ treatment of deafness and blindness in mice; 2) Assessing the cellular effects of USH1C-targeted ASOs and establishing measurable outcomes of treatment efficacy; and 3) Delivering ASOs locally to the mouse cochlea to improve targeting efficacy. The overall goal of these aims is to translate this ASO-targeting approach into a treatment regimen that will lay a foundation for future clinical trials. One far-reaching contribution of this study is the demonstration that ASOs can effectively and potently target the cochlea to rescue hearing, a finding that advocates ASOs as a promising tool for treating diseases of the ear.