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

项目总结/摘要 听力损失是一种日益严重的流行病，据估计，到2050年， 听力困难。听力损失对人类体验的几乎每个方面都有负面影响。 此外，它与促进认知能力下降和痴呆症风险增加有关。的 听力损失最常见的原因是感觉神经性的，如毛细胞和螺旋神经节神经元， 这两种细胞类型对于听觉信息的传递是必不可少的。虽然我们的理解 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的 治疗听力损失的方法远远落后。目前，还没有已知的生物 听力恢复治疗。然而，基于病毒载体的基因治疗策略已经 显示出巨大的潜力。目前，我们对其安全性、有效性和长期 成人耳蜗中的稳定转导仍处于早期阶段。这个应用程序的目标是 通过开发用于基因治疗方法的重组病毒载体来弥合这一差距， 听力损失的治疗因此，我们的目标是生成和表征安全性， 辅助病毒依赖性腺病毒载体的功效和细胞类型特异性转导模式 一个正常的耳蜗和一个退化的耳蜗。我们获得的知识将是 这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.