Gene Therapy for Treating Human Genetic Deafness Tested in Animal Models

 描述(申请人提供)：基因突变是导致所有先天性永久性听力损失病例的一半以上。在学龄儿童中，患病率可能高达每1000人中有6人。缝隙连接(GJ)蛋白的突变(例如，GJB2)会导致一些最常见的人类先天性非综合征性耳聋。遗传易感性也被认为是影响数千万患者的年龄相关性听力损失(ADHL)和噪声性听力损失(NIHL)的重要因素。今天，没有生物治疗来纠正遗传性感音神经性耳聋的根源、细胞和遗传原因。多年来，听力领域的多个研究小组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。最近的报告已经取得了一些有希望的结果；然而，病毒介导的基因治疗在纠正最常见的非综合征性人类遗传性耳聋方面的可行性和可靠性仍有待证实。到目前为止，基因疗法还没有成功地治疗成年阶段的小鼠模型的听力损失。此外，目前尚无治疗感音神经性耳聋的基因治疗研究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体内临床前研究所需的重大实验，该实验用于治疗最常见的非综合征性耳聋以及adhl和nihl。研究将在出生后和成年阶段测试基因治疗的效果。我们将研究使用病毒介导的基因替换/增强疗法在条件性Gjb2-/-、Gjb6-/-和C57BL/6J(研究ADHL和NIHL的流行小鼠模型)小鼠中预防听力损失的可行性和可靠性。我们还将在这些小鼠模型上调查该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将基因治疗转化为临床应用所需的一些重要和必要的步骤。

 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.