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

用于内耳基因治疗方法的辅助依赖性腺病毒载体的开发

基本信息

批准号：
9981782
负责人：
Marlan R Hansen
金额：
$ 19.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981782
关键词：
Acute Adenovirus Protein Adenoviruses Adult Aging Animals Anxiety Architecture Auditory Behavior Biological Response Modifier Therapy Brain CD46 Antigen Capsid Proteins Carrying Capacities Cell Count Cells Chronic Clinical Cochlea Communication Coxsackie Viruses Data Development Epidemic Exhibits Exposure to FDA approved Fiber Functional disorder Gene Delivery Gene Expression Gene Transduction Agent Genes Genetic Goals Hair Cells Health Hearing Human Immune Impaired cognition Infiltration Injections Knowledge Labyrinth Light Liver Lung Measures Mediating Membrane Mental Depression Methods Microscopy Mus Muscle Neurons Noise Non-Viral Vector Operative Surgical Procedures Pattern Pharmaceutical Preparations Receptor Cell Regulatory Element Reporter Retina Safety Scala Tympani Sensorineural Hearing Loss Serotyping Sialic Acids Signal Transduction Specificity Stains Structure of posterior semicircular canal Techniques Technology Therapeutic Time Tissues Toxic effect Translating Tropism Viral Viral Genes Viral Vector Virus Diseases Virus Receptors Work World Health Organization adenoviral-mediated adenovirus receptor base cell type cellular transduction clinically relevant deaf dementia risk effective therapy experience flexibility gene therapy gutless adenoviral vector hearing impairment hearing loss treatment hearing restoration improved knob protein new technology novel novel therapeutic intervention novel therapeutics ototoxicity promoter psychosocial receptor recombinant viral vector round window spiral ganglion success transgene expression treatment strategy vector

项目摘要

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.

项目概要/摘要听力损失是一种日益严重的流行病，估计到 2050 年将有超过 9 亿人患有听力损失听力困难。听力损失几乎对人类经历的各个方面产生负面影响。此外，它还与促进认知能力下降和痴呆风险增加相关。这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，转导听觉信息所必需的两种细胞类型都丢失了。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能力治疗听力损失的治疗方法远远落后。目前尚无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、有效性和长期性的了解成人耳蜗的稳定转导仍处于早期阶段。该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补这一差距治疗听力损失。因此，我们的目标是生成并表征安全性、辅助依赖性腺病毒载体的功效和细胞类型特异性转导模式功能正常的耳蜗和失聪的耳蜗。我们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价值。