Gene Therapy for Usher Syndrome (USH1C)

亚瑟综合症 (USH1C) 基因治疗

• 批准号: 7313819
• 负责人: JEAN BENNETT
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313819
• 关键词: Accounting; Affect; Animal Model; Blindness; Cells; Child; Cochlea; Complementary DNA; Data; Development, Other; Disease; Early Diagnosis; Exposure to; Functional disorder; Gene Delivery; Gene Transfer; Genes; Goals; Health; Hearing; Human; Individual; Information Resources; Inherited; Life; Mediating; Methods; Mus; Mutate; Mutation; Neonatal; Online Mendelian Inheritance In Man; Organ; Outcome; Protein Isoforms; Proteins; Research; Research Personnel; Retinal; Retinitis Pigmentosa; Safety; Screening procedure; Staging; Testing; Therapeutic Effect; Toxic effect; Treatment Efficacy; Usher Syndrome; Viral Vector; base; congenital deafness; deafness; gene therapy; gene therapy clinical trial; hearing impairment; improved; in vivo; interest; mouse model; novel; prevent; programs; skills

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.

描述（由申请人提供）：拟议的研究的广泛长期目标是开发可以在体内成功使用的基因治疗方法，以减慢或预防Usher综合征的耳聋和失明。 仅通过结合两个主要研究人员的独特技能，多样化的科学利益，知识和资源，才能实现这项研究。 他们选择了最严重的Usher综合征，1型（USH1）进行研究，因为这会导致先天性深刻的耳聋，持续的前庭功能障碍和细视性视网膜炎色素（导致失明）（Nicoll等，1988，Aust Nzj ost Nzj ophthalmol 16：205-8-8-8--105-8--195; 33.193; 33; Arcir et and and and and。 Al。 USH1C是一种疾病的常染色体隐性形式，将成为研究的重点：1）这是USH1疾病的很大一部分（33-44％）； 2）USH1C基因编码谐音（也称为PDZ结构域的蛋白质; PDZ73（Omim，2005））可以导致其他（非综合性）遗传的先天性耳聋形式。 3）最近的数据表明，谐蛋白的第一个PDZ结构域（PDZ1）对于五种USH1的蛋白质相互作用至关重要。 4）具有USH1C（Harmonin）突变和先天性耳聋的动物模型。 研究者已经开发出来将基因传递到耳蜗的方法用于优化基因转移到受影响的细胞中，并测试野生型谐音基因递送的治疗作用。 将评估单一治疗人工耳蜗基因治疗的安全性和毒性，以对目标有感觉的感官细胞，靶器官外部细胞的影响以及全身效应进行评估。 这项研究产生的数据将为先天性听力损失的基因治疗提供人类临床试验的平台，这将是改善新生儿听力（和视网膜）筛查程序的激励因素，并应为开发其他基于基因的新型基因治疗的先天性敏感性疾病的疗法提供洞察力。