Gene Therapy for Usher Syndrome (USH1C)

描述（由申请人提供）：拟议研究的广泛，长期目标是开发基因治疗方法，可以成功地在体内用于减缓或预防Usher综合征的耳聋和失明。 这项研究只有通过结合两位主要研究人员的独特技能，不同的科学兴趣，知识和资源才有可能。 他们选择了最严重的Usher综合征1型（USH 1）进行研究，因为这种综合征会导致先天性严重耳聋、持续性前庭功能障碍和青春期前视网膜色素变性（导致失明）（Nicoll等，1988，Aust NZJ Ophthalmol 16：205-8; Armitage等，1995，Arch Dis Child 73：53-6; Admiral等，2000，Int J Pediatr Otorhinolaryngol 55：133-142）。 USH 1C是一种常染色体隐性遗传形式的疾病，将成为研究的重点，因为：1）这占USH 1疾病的很大比例（33-44%）; 2）USH 1C基因，编码协调蛋白，（也称为含PDZ结构域的蛋白; PDZ 73（OMIM，2005））在突变时可以导致其他的免疫缺陷。（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（PDZ 1）对USH 1的五种形式的蛋白质的相互作用至关重要;和4）具有Ush 1c（harmonin）突变和先天性耳聋的动物模型是可用的。 研究人员已经开发出将基因传递到耳蜗的方法，用于优化向受影响细胞的基因转移，并测试野生型harmonin基因传递的治疗效果。 单次治疗耳蜗基因疗法的安全性和毒性将在对靶感觉神经细胞的影响、暴露于靶器官外的细胞和全身效应方面进行评价。 这项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）筛查计划的激励因素，并应为开发其他新的基于基因的先天性感觉神经疾病治疗方法提供基础。

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.