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。这个 可以包括鼓膜切开术和/或鼓膜造口管插入，以提供通气并允许穿透 局部药物通过膜。局部药物治疗已被证实非常有效 治疗中耳炎。然而，对于儿童来说，破膜需要全身麻醉。此外，任何 涉及手术的治疗费用昂贵，而且在世界部分地区并不实用，会导致听力损失和 许多发展中国家因中耳炎死亡。加强中耳疾病的医疗治疗， 我们使用噬菌体展示肽文库的顺序选择来鉴定跨越 运输货物时通过主动过程鼓膜。携带这些肽之一的噬菌体 进入中耳的速度是非目标噬菌体的 106-7 倍。肽也可以跨膜 独立于噬菌体。我们通过延长肽长度、鉴定氨基酸来优化递送 与快速转运相关的序列、基序，证明了跨越人类鼓膜的转运，以及 获得了有关运输机制的重要证据。然而，存在许多障碍 转化为临床使用。反式TM肽运输的长期安全性和有效性需要 评价。应开发一种长期交付的实用方法。肽介导的应用 应探索采用大型药品包装运输。应该更好地理解传输机制。 是否存在比在动物中发现的肽更有效地通过人类 TM 运输的肽 型号，应确定。最后，应确认药物通过人类 TM 的传递。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。 经鼓室药物输送将实现更高的中耳药物水平并避免副作用或脱靶效应， 与全身药物相比。该方法将在治疗中得到广泛应用 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.