Improved Micro-Technologies for Inner Ear Drug Delivery

描述（由申请人提供）：候选人将运用其MEMs和生物医学工程背景研究和治疗耳聋和听觉功能障碍。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。他打算为成功创建有效的耳聋治疗方法提供关键的工程观点和方法，这些治疗方法经过临床测试并最终批准用于人类临床应用。为了实现这一目标，候选人需要在听觉系统功能和病理、脊椎动物研究和基于基因的治疗等领域接受额外的培训和指导。这将通过课程作业、研讨会、会议以及与导师及其多学科研究团队的密切互动来完成。恢复正常听觉功能的高级耳聋治疗将需要在一段时间内仔细地定时和剂量，定向地递送几种基因载体和/或化合物。该候选人计划通过三个具体目标来推进遗传控制小鼠模型系统中的耳聋治疗研究：(1)开发优化的剂量配置，在3-48 kHz范围内实现lacZ报告基因在整个耳蜗中的有效表达，同时保持耳蜗的传入和传出功能；(2)研制并评价符合小鼠耳廓尺寸限制，满足耳蜗内药物输送要求的植入式微泵平台；(3)确定重复人工耳蜗输注的影响，为更复杂的耳聋治疗提供指导。永久性感音神经性听力损失和耳聋影响现代社会10%以上的人口，影响65岁及以上人口的比例超过50%。内耳的基因治疗研究有可能纠正主要的慢性医学疾病，如与年龄有关的听力损失，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，要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转化结果，需要制定详细的方案。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.