Improved Micro-Technologies for Inner Ear Drug Delivery

应聘者描述(申请人提供)：应聘者将运用他的MEMS和生物医学工程背景来研究和治疗耳聋和听力障碍。他的目标是成为脊椎动物研究、听觉系统病理学和基于基因疗法的校准交付方面的工程专家。他打算为成功创建经过临床测试并最终批准用于人类临床的有效耳聋治疗方法贡献一种关键的工程学观点和方法。为了实现这一目标，候选人需要在听觉系统功能和病理学、脊椎动物研究和基于基因的疗法领域进行额外的培训和指导。这将通过课程、研讨会、会议以及与导师和他的多学科研究团队的密切互动来实现。恢复正常听觉功能的先进耳聋疗法需要在一段时间内仔细选择时间和剂量，并在一定时间内定点输送几个基因载体和/或化合物。候选人打算通过三个具体目标推进基因控制的小鼠模型系统的耳聋治疗研究：(1)开发优化的剂量分布，以实现LacZ报告基因在成年小鼠耳蜗中的有效表达，同时保持3-48 kHz的耳蜗传入和传出功能；(2)开发和评估符合小鼠耳朵大小限制的植入式微泵平台，以满足耳蜗内给药的要求；以及(3)确定重复耳蜗液注入的影响，以作为更复杂耳聋治疗的指南。在现代社会，永久性感音神经性听力损失和耳聋影响着超过10%的人口，超过50%的65岁及以上人群。对内耳的基因治疗研究有可能纠正主要的慢性医学疾病，如与年龄相关的听力损失、年龄引起的平衡问题以及其他形式的永久性听力损失和耳聋。疾病状态的复杂性表明，为了在动物模型中实现听力的完全恢复，以及在人类临床试验中获得翻译结果，需要制定详细的方案。这项拟议的研究将提供信息、工具和新的能力，对推进基于耳蜗内基因的治疗研究至关重要。

DESCRIPTION (provided by applicant): The candidate will apply his MEMs and biomedical engineering background to the study and treatment of deafness and auditory dysfunction. He aims to become an engineering expert in vertebrate animal research, auditory system pathologies, and calibrated delivery of gene-based therapies. He intends to contribute a critical engineering perspective and approach to successful creation of effective deafness therapies that are clinically tested and ultimately approved for human clinical use. To achieve this goal, the candidate requires additional training and mentorship in the areas of auditory system function and pathology, vertebrate animal research, and gene based therapies. This will be accomplished through a combination of coursework, seminars, conferences, and close interaction with the mentor and his multidisciplinary research team. Advanced deafness therapies that restore normal auditory function will require carefully timed and dosed, site-directed delivery of several gene vectors and/or compounds over a period of time. The candidate intends to advance deafness therapy research in the genetically controlled mouse model system through three Specific Aims: (1) develop an optimized dosing profile that achieves effective expression of lacZ reporter gene throughout the cochlea in the adult mouse while preserving afferent and efferent cochlear function from 3-48 kHz; (2) develop and evaluate an implantable micropump platform consistent with the size limitations of the mouse ear which meets, the requirements of intra-cochlear drug agent delivery; and (3) determine the impact of repetitive cochlear infusions to act as a guide for more complex deafness therapies. Permanent sensorineural hearing loss and deafness impact over 10% of the population in modern societies and in excess of 50% of those age 65 and older. Gene therapy investigations of the inner ear have the potential to correct major chronic medical disorders such as age-related hearing loss, age-induced balance problems, and other forms of permanent hearing loss and deafness. The complexity of disease states suggests elaborate protocols will be needed to achieve full restoration of hearing in animal models, and for translational results in human clinical trials. The proposed research will provide information, tools, and new capabilities critical for the advancement of intra-cochlear gene-based therapy research.