权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Gene Therapy for Treating Human Genetic Deafness Tested in Animal Models

治疗人类遗传性耳聋的基因疗法在动物模型中进行了测试

基本信息

批准号：
9030530
负责人：
XI LIN
金额：
$ 48.18万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-10 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030530
关键词：
Adult Adverse effects Affect Animal Model Animals Apoptosis Auditory Brainstem Responses BIRC4 gene Basilar Membrane Biological Response Modifier Therapy Birth Cell Count Child Cochlea Cochlear duct Code Connexins DNA Sequence Alteration Data Development Feasibility Studies Functional Imaging GJB2 gene GJB6 gene Gene Expression Genes Genetic Genetic Predisposition to Disease Genotype Green Fluorescent Proteins Hair Cells Health Hearing Histology Human Human Genetics In Vitro Inherited Injection of therapeutic agent Labyrinth Left Long-Term Effects Mediating Monitor Mus Mutation Noise-Induced Hearing Loss Patients Pattern Phenotype Plant Roots Prevalence Prevention Reporter Genes Reporting Research Route Safety Scala Tympani School-Age Population Sensorineural Hearing Loss Staging Testing Therapeutic Effect Time Toxic effect Transgenic Mice Translations Variant Viral Viral Vector Virus Western Blotting Work age related clinical application congenital deafness critical period deafness design efficacy testing gene function gene replacement gene therapy hearing impairment in vivo mouse model null mutation otoacoustic emission overexpression postnatal pre-clinical preclinical study preclinical trial prevent ranpirnase research study response round window success transduction efficiency treatment effect

项目摘要

DESCRIPTION (provided by applicant): Genetic mutations are responsible for more than half of all congenital permanent hearing loss cases. The prevalence can be as high as 6 per 1,000 among school-age children. Mutations in the gap junction (GJ) proteins (e.g., GJB2) cause some of the most common forms of human congenital non-syndromic deafness. Genetic predisposition is also known to be an essential factor in age-dependent hearing loss (ADHL) and noise-induced hearing loss (NIHL), which affect tens of millions of patients. Today there is no biological treatment to correct the root cellular and genetic causes of inherited sensorineural hearing loss. Multiple research groups in the hearing field have worked for years to introduce gene therapy into clinical applications for the treatment of sensorineural deafness. Recent reports have yielded some promising results; however, the in vivo feasibility and reliability of virally mediated gene therapy in correcting the most common forms of non-syndromic human inherited deafness remain to be demonstrated. To date, gene therapy has not been successful at treating hearing loss in adult-stage mouse models. Moreover, none of the gene therapy studies for treating sensorineural hearing loss have advanced to the stage of systematic in vivo preclinical trials yet. The present project is the first to conduct major experiments required for n vivo preclinical studies of a gene therapy approach for treating the most common forms of non-syndromic deafness, as well as ADHL and NIHL, using mouse models. Studies will test the efficacy of gene therapy at both the postnatal and adult stages. We will study the feasibility and reliability of using a virally mediated gene replacement/augmentation therapy to prevent hearing loss in conditional Gjb2-/-, Gjb6-/-, and C57BL/6J (a popular mouse model for studying ADHL and NIHL) mice. We will also investigate the long-term efficacy and safety of the treatment in these mouse models. Carrying out the specific aims outlined here should fulfill some of the vital and necessary steps required for the translation of gene therapy into clinical applications.

描述（由申请人提供）：基因突变是导致一半以上先天性永久性听力损失病例的原因。学龄儿童中的发病率可高达千分之六。差距连接（GJ）蛋白中的突变（例如，GJB 2）引起一些最常见形式的人类先天性非综合征性耳聋。遗传易感性也是年龄依赖性听力损失（ADHL）和噪声性听力损失（NIHL）的重要因素，影响数千万患者。今天，没有生物治疗来纠正遗传性感音神经性听力损失的根本细胞和遗传原因。听力领域的多个研究小组多年来一直致力于将基因治疗引入感音神经性耳聋的临床应用。最近的报告已经取得了一些有希望的结果，但是，在体内的可行性和可靠性的病毒介导的基因治疗，在纠正最常见的形式的非综合征型人类遗传性耳聋仍有待证明。到目前为止，基因治疗在成年小鼠模型中治疗听力损失还没有成功。此外，用于治疗感音神经性听力损失的基因治疗研究还没有进展到系统的体内临床前试验阶段。目前的项目是第一个使用小鼠模型进行基因治疗方法治疗最常见形式的非综合征性耳聋以及ADHL和NIHL的体内临床前研究所需的主要实验。研究将测试基因治疗在出生后和成年阶段的功效。我们将研究使用病毒介导的基因替代/增强疗法预防条件性Gjb 2-/-、Gjb 6-/-和C57 BL/6 J（一种研究ADHL和NIHL的流行小鼠模型）小鼠听力损失的可行性和可靠性。我们还将在这些小鼠模型中研究治疗的长期有效性和安全性。执行这里概述的具体目标应该完成一些将基因治疗转化为临床应用所需的重要和必要步骤。