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一种治愈性治疗先天性耳聋，前庭功能障碍和视网膜色素变性的Usher综合征，主要的遗传原因组合耳聋和失明。这种治疗方法最终可能被开发为一般听力，平衡和视力丧失的治疗方法。在这个项目中，我们研究使用反义寡核苷酸（ASOs）治疗小鼠Usher综合征。我们设计了一种阿索来纠正USH 1C基因突变引起的RNA剪接缺陷，USH 1C基因突变导致小鼠和人类出现Usher综合征。初步结果表明，USH 1C靶向阿索可以挽救小鼠的听力和前庭功能。该项目的目的是通过以下方式进一步发展这种ASO靶向方法：1）开发基于ASO的治疗方案，用于预防/治疗小鼠耳聋和失明; 2）评估USH 1C靶向ASO的细胞效应，并建立可测量的治疗疗效结果; 3）将ASO局部递送至小鼠耳蜗，以提高靶向疗效。这些目标的总体目标是将这种ASO靶向方法转化为治疗方案，为未来的临床试验奠定基础。这项研究的一个意义深远的贡献是证明了ASO可以有效地和有力地靶向耳蜗以拯救听力，这一发现倡导ASO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.