Gene Therapy for Treating Human Genetic Deafness Tested in Animal Models

 描述（由申请人提供）： 一半以上的先天性永久性听力损失病例是由基因突变造成的。在学龄儿童中，患病率可高达千分之六。间隙连接 (GJ) 蛋白（例如 GJB2）的突变会导致一些最常见的人类先天性非综合征性耳聋。遗传易感性也是导致年龄依赖性听力损失 (ADHL) 和噪声性听力损失 (NIHL) 的重要因素，影响着数千万患者。如今，还没有生物治疗方法可以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疗法引入临床应用以治疗感音神经性耳聋。最近的报告取得了一些有希望的结果；然而，病毒介导的基因疗法在纠正最常见形式的非综合征性人类遗传性耳聋方面的体内可行性和可靠性仍有待证明。迄今为止，基因疗法尚未成功治疗成年小鼠模型的听力损失。此外，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。本项目是第一个使用小鼠模型进行基因治疗方法体内临床前研究所需的主要实验，用于治疗最常见形式的非综合征性耳聋以及 ADHL 和 NIHL。研究将测试基因治疗在产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/增强疗法来预防条件性 Gjb2-/-、Gjb6-/- 和 C57BL/6J（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。我们还将研究这些小鼠模型中治疗的长期疗效和安全性。实现此处概述的具体目标应实现将基因治疗转化为临床应用所需的一些重要且必要的步骤。

 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.