Vestibular dysfunction and the development of therapies for Usher syndrome

前庭功能障碍和 Usher 综合征疗法的发展

基本信息

批准号：
10579518
负责人：
Gwenaelle S Geleoc
金额：
$ 66.51万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579518
关键词：
1 year old Address Adult Affect Age Age Months Aging Antisense Oligonucleotide Therapy Behavioral Biological Markers Blindness Canada Childhood Clinic Clinical Clinical Trials Communication Disease Disease Progression Dose Ear Diseases Effectiveness Equilibrium Evoked Potentials Exhibits Foundations Frequencies Functional disorder Future Genes Genetic Goals Hair Cells Head Health Hearing Human Impairment Knock-in Mouse Knowledge Lead Length Life Longevity Louisiana Measurable Measures Medical Messenger RNA Molecular Morphology Mus Mutation National Institute on Deafness and Other Communication Disorders Natural History Neonatal Organ Outcome Patients Pediatric cohort Persons Population Proteins RNA Splicing Rare Diseases Research Support Retinitis Pigmentosa Rotation Saccule structure Sensory Testing Therapeutic Therapeutic Effect Time Tissues Translations Treatment Efficacy Treatment Protocols USH1C gene Usher Syndrome Usher Syndrome Type 1 Usher Syndrome Type 1C Variant Vestibular Hair Cells Vision adeno-associated viral vector age related clinical outcome measures cohort deafness drug candidate effective therapy efficacy evaluation equilibration disorder first-in-human gene replacement gene replacement therapy gene therapy hearing impairment human study interest mouse model multisensory neurophysiology novel optimal treatments otoconia prevent prospective therapeutic evaluation therapy development transcriptome sequencing treatment strategy vestibulo-ocular reflex young adult

项目摘要

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.

项目概要总的来说，罕见疾病影响着世界上约 3.5 亿人，其中大多数缺乏特异性治疗方法导致巨大的医疗需求得不到满足。了解潜在的遗传和分子机制和开发罕见疾病疗法对于我们努力解决这一紧迫问题至关重要需要。本申请的重点是了解和治疗亚瑟综合症（Usher），一种罕见疾病其特点是多感官丧失（听力、视觉和平衡），从而造成主要的沟通和影响生活各个方面的出行负担。目前，没有任何治疗方法可以预防或减缓亚瑟的进展。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情况路易斯安那州和加拿大阿卡迪亚人群中常见的 1 型 Usher 突变 (USH1C c.216G>A)（目的 1) 并在儿科、青年和成年 USH1C 患者队列中进行研究（目标 3），并测试治疗效果反义疗法和基因替代疗法在疾病不同阶段的疗效 USH1C 小鼠的进展（目标 2）。这些目标是由 USH1C 相关的中心假设驱动的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，这是我们强大的支持初步研究表明，前庭眼反射随年龄的增长而下降，并且进行性衰退 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来定义前庭的进展 USH1C 小鼠在 1 年的时间过程中出现功能障碍。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 小鼠中发挥功能，并进一步测试其功能在疾病进展的各个阶段提供的有效性。与此同时，在目标 3 中，我们将定义通过测试 50 名 USH1C 患者的前庭功能，了解其前庭功能障碍的自然史基线和 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果指标。结果由此合作项目将确定主要临床候选药物，以及恢复健康的最佳治疗方案 USH1C 小鼠的前庭功能，并定义可测量的临床结果来指导首次人体研究一种治疗 USH1C 前庭功能障碍的方法。