Gene Therapy for Usher Syndrome (USH1C)

描述（由申请人提供）：拟议研究的广泛，长期目标是开发可在体内成功使用的基因治疗方法，以减缓或预防Usher综合征的耳聋和失明。只有结合两位关键研究者的独特技能、不同的科学兴趣、知识和资源，这项研究才有可能。他们选择了Usher综合征最严重的1型（USH1）进行研究，因为它会导致先天性深度耳聋、持续性前庭功能障碍和青春期前发生的视网膜色素变性（导致失明）（Nicoll等人，1988年，Aust NZJ Ophthalmol 16:205-8； Armitage等人，1995年，Arch Dis Child 73:53-6； Admiral等人，2000年，Int J pediatrics Otorhinolaryngol 55:133-142）。USH1C是一种常染色体隐性形式的疾病，将成为研究的重点，因为：1)它占USH1疾病的很大比例（33-44%）；2)编码和谐蛋白（也称为PDZ结构域蛋白；PDZ73 (OMIM, 2005)）的USH1C基因在发生突变时，可导致其他（非综合征）遗传形式的先天性耳聋；3)最近的数据表明，harmonin的第一个PDZ结构域（PDZ1）对5种USH1s蛋白的相互作用至关重要；4)有Ush1c （harmonin）突变和先天性耳聋的动物模型。研究人员开发了将基因传递到耳蜗的方法，以优化基因转移到受影响的细胞并测试传递野生型和声素基因的治疗效果。单次耳蜗基因治疗的安全性和毒性将根据对靶感音神经细胞的影响、对靶器官外细胞的暴露以及全身效应进行评估。本研究的数据将为先天性听力损失基因治疗的人类临床试验提供平台，这将是改善新生儿听力（和视网膜）筛查计划的一个激励因素，并为先天性感觉神经疾病的其他新型基因治疗的发展提供基础。

DESCRIPTION (provided by applicant): The broad, long-term goal of the proposed research is to develop gene therapy approaches that can be used successfully in vivo to slow or prevent deafness and blindness in Usher syndrome. This study is made possible only by combining the unique skills, diverse scientific interests, knowledge, and resources of the two key investigators. They have selected the most severe form of Usher syndrome, type 1 (USH1), for study as this causes congenital profound deafness, constant vestibular dysfunction, and prepubertal onset retinitis pigmentosa (leading to blindness) (Nicoll et al. 1988, Aust NZJ Ophthalmol 16:205-8; Armitage et al. 1995, Arch Dis Child 73:53-6; Admiral et al. 2000, Int J Pediatr Otorhinolaryngol 55:133-142). USH1C, an autosomal recessive form of the disease, will be the focus of the studies since: 1) this accounts for a significant percentage of USH1 disease (33-44%); 2) the USH1C gene, which encodes harmonin (also known as PDZ domain-containing protein; PDZ73 (OMIM, 2005)) can, when mutated, result in other (non-syndromic) inherited forms of congenital deafness; 3) recent data indicate that the first PDZ domain (PDZ1) of harmonin is critical to the interaction of proteins underlying five forms of USH1s; and 4) animal models with Ush1c (harmonin) mutations and congenital deafness are available. Methods the investigators have developed to deliver genes to the cochlea are used to optimize gene transfer to the affected cells and test therapeutic effects of delivery of the wild-type harmonin gene. Safety and toxicity of single treatment cochlear gene therapy will be evaluated with respect to effects on target sensorineural cells, exposure to cells outside of the target organ, and systemic effects. The data resulting from this study will provide the platform for a human clinical trial for gene therapy for congenital hearing loss, which will be a motivating factor for improving neonatal hearing (and retinal) screening programs, and should provide the groundwork for development of other novel gene-based treatments for congenital sensorineural disease.