Innovative therapy for diseases of the middle ear

摘要 慢性中耳炎的治疗通常涉及破坏鼓膜(TM)的完整性。这 可以包括鼓室切开术和/或鼓室造瘘管插入，这提供了通风并允许穿透 外用药物通过膜。当地的药物治疗已被发现对 治疗中耳炎。然而，在儿童中，打破膜需要全身麻醉。此外，任何 涉及手术的治疗费用昂贵，在世界上一些地区也不实用，导致听力损失和 在许多发展中国家，死于中耳炎。为了加强中耳疾病的医疗治疗， 我们使用噬菌体展示多肽文库的顺序选择来识别罕见的、新的跨越 在运输货物时，鼓膜通过一个活跃的过程。携带这些多肽之一的噬菌体 进入中耳的速度是非靶向噬菌体的106-7倍。这些多肽也能穿过细胞膜。 与噬菌体无关。我们已经通过延长多肽长度来优化递送，确定了氨基酸 序列，与快速运输相关的基序，显示了跨越人类鼓膜的运输和 获得了关于运输机制的重要证据。然而，要做到这一点，存在许多障碍 转化为临床应用。反式TM多肽转运的长期安全性和有效性有待于 已评估。应该制定一种长期交付的实用方法。多肽介导剂的应用 应该探索向大包装药品的运输。应该更好地理解运输机制。 是否存在比在动物体内发现的更有效地通过人类TM运输的多肽 模型，应该被确定。最后，药物在人类TM中的传递应该得到确认。这个 拟议的研究将进一步开发一种治疗中耳疾病的全新范式。 经鼓室给药将达到更高的中耳药物水平，并避免副作用或靶外效应， 与全身用药相比。这种方法学将在治疗上有广泛的应用 中耳炎和其他中耳疾病。

ABSTRACT Treatment for chronic otitis media often involves breaching the integrity of the tympanic membrane (TM). This can include tympanotomy and/or tympanostomy tube insertion, which provide aeration and allow the penetration of topical medications through the membrane. Local drug treatment has been found to be highly effective in treating otitis. However, in children, breaching the membrane requires general anesthesia. Moreover, any treatment involving surgery is expensive and in parts of the world is not practical, leading to hearing loss and deaths due to otitis media in many developing countries. To enhance medical treatment of middle ear disorders, we used sequential selection of phage-display peptide libraries to identify rare, novel peptides that cross the tympanic membrane via an active process while transporting cargo. Bacteriophage bearing one of these peptides enters the middle ear at 106-7 times the rate of an untargeted phage. The peptides also cross the membrane independent of phage. We have optimized delivery by extension of peptide length, identified amino acid sequence, motifs linked to rapid transit, demonstrated transit across the human tympanic membrane and obtained important evidence regarding the mechanism of transport. However, a number of barriers exist to translation into clinical usage. Longer-term safety and efficacy of trans-TM peptides transport needs to be evaluated. A practical method for long-term delivery should be developed. Application of peptide-mediated transport to large drug packages should be explored. The transport mechanism should be better understood. Whether there are more efficient peptides for transport across the human TM, than those discovered in animal models, should be determined. Finally, delivery of medications across the human TM should be confirmed. The proposed research will further develop 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.