Vestibular dysfunction and the development of therapies for Usher syndrome

项目摘要 总的来说，罕见疾病影响着世界上约3.5亿人，其中大多数缺乏具体的治疗方法 导致巨大的医疗需求未得到满足。了解潜在的遗传和分子 机制和开发罕见疾病的疗法对于我们努力解决这一紧迫问题至关重要。 需要的本申请集中于理解和治疗Usher综合征（Usher），一种罕见疾病， 以多感官丧失（听觉、视觉和平衡）为特征， 流动性负担影响生活的各个方面。目前，还没有治疗方法来预防或减缓 Usher的进展为了填补这些重要的空白，我们在这个合作项目中提出了三个目标， 在敲入小鼠模型中确定前庭功能障碍随时间的进展， 在路易斯安那州和加拿大的印第安人群体中常见的1型Usher突变（USH1C c.216G>A）（目的 1)以及在儿童、年轻成人和成人USH1C患者队列中（目的3），并测试治疗效果。 反义和基因替代疗法在不同疾病阶段的疗效 在USH1C小鼠中的进展（Aim 2）。这些目标是由中心假设驱动的，即USH1C相关 前庭功能障碍随着时间的推移而进展，并且是终末器官特异性的，这得到了我们强有力的证据的支持。 初步研究显示前庭眼反射的年龄依赖性下降， USH1C小鼠的囊状毛细胞变性。在目标1中，我们将采用分子，结构， 单一前庭传入神经生理学和行为生物标志物，以确定前庭 USH1C小鼠在1年时间过程中的功能障碍。在目标2中，我们将继续研究恢复前庭功能， 使用反义和基因替代疗法在新生USH1C小鼠中的功能，并进一步测试它们的 在疾病进展的各个阶段提供时的有效性。在目标3中，我们将定义 通过测试50名USH1C患者的前庭功能， 基线和6个月后。这些结果将填补理解和治疗亚瑟的重要空白 疾病，并允许我们为未来的临床试验定义临床结局指标。结果从这个 合作项目将确定领先的临床候选药物，一个最佳的治疗方案， USH1C小鼠的前庭功能，并定义可测量的临床结果，以指导首次在人体内进行的 USH1C中前庭功能障碍的治疗。

Project Summary Collectively, rare diseases affect ~350 million people in the world, and most of them lack specific treatments resulting in a tremendous unmet medical need. Understanding the underlying genetic and molecular mechanisms and developing therapies for rare diseases are essential for our efforts to address this urgent need. The present application focuses on understanding and treating Usher syndrome (Usher), a rare disease characterized by multisensory loss (hearing, vision, and balance) that creates a major communication and mobility burden affecting all aspects of life. Currently, there are no treatments to prevent or slow the progression of Usher. To fill these important gaps, we propose three aims in this collaborative project to determine the progression of vestibular dysfunction over time in the knock-in mouse model for the most common type 1 Usher mutation in the Acadian populations of Louisiana and Canada (USH1C c.216G>A) (Aim 1) and in a cohort of pediatric, young adult, and adult USH1C patients (Aim 3), and to test the therapeutic efficacies of antisense and gene replacement therapies when delivered at different stages of disease progression in the USH1C mice (Aim 2). These aims are driven by the central hypothesis that USH1C-related vestibular dysfunction progresses over time and is end-organ specific, which is supported by our strong preliminary studies that show age-dependent declines of the vestibulo-ocular reflexes, and progressive saccular hair cell degeneration in USH1C mice. In Aim 1, we will employ a combination of molecular, structural, single vestibular afferent neurophysiology, and behavioral biomarkers to define the progression of vestibular dysfunction in USH1C mice over a 1-year time course. In Aim 2, we will continue studies to restoring vestibular function in neonatal USH1C mice using the antisense and gene replacement therapies and further test their effectiveness when delivered at various stages of disease progression. In parallel, in Aim 3, we will define the natural history of vestibular dysfunction in a cohort of 50 USH1C patients by testing their vestibular function at baseline and 6 months later. These results will fill the important gaps in understanding and treating Usher disease and allow us to define the clinical outcome measures for future clinical trials. Results from this collaborative project will identify lead clinical drug candidates, an optimal treatment regimen for restoring vestibular function in USH1C mice, and define measurable clinical outcomes to guide a first-in-human study of a treatment for vestibular dysfunction in USH1C.