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 可包括鼓膜切开术和/或鼓膜造口管插入，其提供通气并允许穿透 局部药物的渗透当地药物治疗已被发现是非常有效的， 治疗耳炎。然而，在儿童中，破膜需要全身麻醉。此外，任何 涉及手术的治疗是昂贵的，并且在世界上的部分地区是不实际的，导致听力损失， 许多发展中国家因中耳炎而死亡。为了加强中耳疾病的医疗， 我们使用噬菌体展示肽库的顺序选择来鉴定罕见的、新的肽， 在运输货物时通过主动过程破坏鼓膜。噬菌体带有这些肽之一的噬菌体 进入中耳的速度是非靶向噬菌体的106-7倍。这些肽也能穿过细胞膜 不依赖于噬菌体。我们已经通过延长肽长度优化了递送，鉴定了氨基酸 序列，基序连接到快速运输，证明运输通过人类鼓膜， 获得了有关运输机制的重要证据。然而，存在着一些障碍， 转化为临床应用。trans-TM肽转运的长期安全性和有效性需要进一步研究。 评估。应制定一种长期执行的切实可行的方法。肽介导的应用 应探讨如何运输到大型药包。应更好地理解运输机制。 是否有比动物中发现的更有效的肽用于跨人类TM的运输， 模型，必须确定。最后，应确认药物穿过人TM的递送。的 拟议的研究将进一步开发一种治疗中耳疾病的全新范例。 经鼓膜药物递送将实现更高的中耳药物水平并避免副作用或脱靶效应， 与全身性药物相比。这种方法将广泛应用于治疗 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.