Development of Helper Dependent Adenoviral Vectors for Inner Ear Gene Therapy Approaches

项目摘要/摘要 听力损失是一种日益严重的流行病，据估计，到2050年，将有超过9亿人患有听力损失 听力有困难。听力损失几乎对人类体验的方方面面都有负面影响。 此外，它还与促进认知能力下降和增加患痴呆症的风险有关。这个 最常见的听力损失原因是感觉神经细胞，如毛细胞和螺旋神经节神经元， 传递听觉信息所必需的两种细胞类型已经丢失。虽然我们的理解是 调节毛细胞和螺旋神经节神经元的基因和信号级联 继续以爆炸性的速度增长，将这些知识转化为有效 治疗听力损失的方法远远落后。目前，还没有已知的生物学 听力恢复治疗。然而，基于病毒载体的基因治疗策略已经 展现出了巨大的潜力。目前，我们对它们的安全性、有效性和长期疗效的了解 在成年耳蜗体内的稳定转导仍处于早期阶段。此应用程序的目标是 为了弥合这一差距，我们开发了一种用于基因治疗的重组病毒载体 听力损失的治疗。因此，我们的目标将是产生和表征安全性， 辅助者依赖型腺病毒载体的有效性和细胞类型特异性转导模式 一个功能正常的耳蜗和一个耳聋的耳蜗。我们所获得的知识将是 对于开发有效的内耳基因治疗方法具有巨大的价值。

Project Summary/Abstract Hearing loss is a growing epidemic with estimates that by 2050 over 900 million people will have difficulty hearing. Hearing loss negatively impacts almost every aspect of the human experience. In addition, it is correlated to promoting cognitive decline and increased risk of dementia. The most common cause of hearing loss is sensorineural as hair cells and spiral ganglion neurons, the two cell types essential for transducing auditory information, are lost. While our understanding of the genes and the signaling cascades that regulate hair cells and spiral ganglion neurons continues to grow at an explosive pace, the ability to translate this knowledge into effective treatments for curing hearing loss lags far behind. Currently, there is no known biological treatment for hearing restoration. However, viral vector-based gene therapy strategies have shown tremendous potential. Currently, our understanding of their safety, efficacy, and long-term stable transduction in the adult cochlea is still in the early stages. The goal of this application is to bridge this gap by developing a recombinant viral vector for gene therapy approaches for the treatment of hearing loss. Therefore, our objective will be to generate and characterize the safety, efficacy, and cell type-specific transduction patterns of a helper-dependent adenovirus vector in a normal functioning cochlea and a deafened cochlea. Our knowledge gained will be of tremendous value for the development of effective gene therapy approaches in the inner ear.