Innovative therapy for diseases of the middle ear

描述(申请人提供)：慢性中耳炎的治疗通常需要手术，包括鼓膜造口术，它提供空气并允许局部药物通过鼓膜渗透。这种局部药物治疗已被发现非常有效。然而，手术费用昂贵，而且在世界许多地区不切实际，在发展中国家导致听力损失和中耳炎死亡。为了加强中耳疾病的医疗治疗，我们使用噬菌体展示肽库的顺序选择来识别罕见的、新的多肽，这些多肽在运输货物时活跃地穿过鼓膜。初步数据表明，携带这些多肽之一的噬菌体进入中耳的速度是非靶标噬菌体的106倍。我们建议通过确定所有已识别的多肽的跨鼓室转运速率和饱和水平来扩展这项工作。我们将评估经鼓室多肽暴露后的外耳、鼓膜和中耳，以确定是否有任何不良反应，并评估多肽携带药物和影响中耳感染的能力。 我们还将确定这些多肽是否穿过人类鼓膜，并鉴定介导跨鼓室运输的结合伙伴。这项拟议的研究将为中耳疾病的治疗带来一种全新的范式。与全身用药相比，经鼓室给药可以达到更高的中耳药物水平，并避免副作用或靶外效应。这种方法将在中耳炎和其他中耳疾病的治疗中得到广泛应用。 公共卫生相关性：这一转化研究项目寻求通过开发通过鼓膜主动递送药物的方法来改进中耳炎和其他中耳疾病的治疗。这个项目将建立在我们最近发现的稀有多肽的基础上，这些多肽可以在连接到噬菌体的同时快速穿过鼓膜，开发能够主动将药物输送到人类中耳的载体。如果成功，该项目将建立一种全新的中耳炎治疗策略，例如，将避免全身副作用和非靶标细菌对抗生素的暴露。

DESCRIPTION (provided by applicant): Treatment for chronic otitis media often involves surgery, including tympanostomy tubes which provide aeration and allow the penetration of topical medications through the tympanic membrane. Such local drug treatment has been found to be highly effective. However, surgery is expensive and in many parts of the world is not practical, leading to hearing loss and deaths due to otitis media in the developing world. To enhance medical treatment of middle ear disorders, we used sequential selection of phage-display peptide libraries to identify rare, novel peptides that actively cross the tympanic membrane while transporting cargo. Preliminary data indicate that a bacteriophage bearing one of these peptides enters the middle ear at 106 times the rate of an untargeted phage. We propose to extend this work by determining the rate and saturation level of transtympanic transport for all identified peptides. We will evaluate the external ear, tympanic membrane and middle ear after transtympanic peptide exposure, to determine whether there are any adverse effects, and assess the ability of peptides to carry drugs and to influence a middle ear infection. We will also determine whether these peptides cross the human tympanic membrane, and characterize the binding partners that mediate transtympanic transport. The proposed research will lead to an entirely novel paradigm for the treatment of middle ear diseases. Transtympanic drug delivery would achieve higher middle ear drug levels and avoid side- or off-target effects, when compared to systemic medications. This methodology will have widespread applications for the treatment of otitis media and other middle ear conditions. PUBLIC HEALTH RELEVANCE: This translational research project seeks to improve the treatment of otitis media and other disorders of the middle ear, by developing methods for active delivery of medications through the tympanic membrane. This project will build upon our recent discovery of rare peptides that can rapidly transit the tympanic membrane while attached to bacteriophage, to develop carriers that can actively transport drugs into the human middle ear. If successful, this project will establish an entirely novel therapeutic strategy for otitis media, on that will, for example, avoid systemic side effects and exposure of off-target bacteria to antibiotics.