Innovative therapy for diseases of the middle ear

中耳疾病的创新疗法

• 批准号: 10360495
• 负责人: Allen F. Ryan
• 金额: $ 33.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360495
• 关键词: Active Biological Transport; Acute; Age; Amino Acid Sequence; Anesthesia procedures; Animal Model; Antibiotics; Bacteria; Bacteriophages; Basic Science; Binding; Biological; Cessation of life; Child; Chronic; Clinical; Developing Countries; Disadvantaged; Drug Delivery Systems; Drug Transport; Excision; Family; General Anesthesia; Health; Hour; Human; Hydrogels; Innovative Therapy; Labyrinth; Length; Ligands; Link; Mediating; Medical; Membrane; Methodology; Methods; Operative Surgical Procedures; Otitis; Otitis Media; Patient observation; Penetration; Peptide Library; Peptide Phage Display Library; Peptide Transport; Peptides; Phage Display; Pharmaceutical Preparations; Pharmacotherapy; Process; Property; Proteins; Public Health; Research; Research Project Grants; Safety; Side; Structure; Surface; Techniques; Therapeutic; Time; Translating; Translational Research; Translations; Treatment Cost; Treatment Failure; Tympanic membrane; Tympanostomy; Tympanostomy Tube Insertions; active method; alternative treatment; clinical application; dosage; gene therapy; hearing impairment; improved; in vitro Assay; industry partner; innovation; local drug delivery; middle ear; middle ear conditions; middle ear disorder; novel; preservation; programs; side effect; transcriptome sequencing; transcytosis

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.

抽象的 慢性中耳炎的治疗通常涉及破坏鼓膜（TM）的完整性。这 可以包括鼓膜切开术和/或鼓膜切开术插入，可提供充气并允许穿透 通过膜的局部药物。已发现局部药物治疗在 治疗中耳炎。但是，在儿童中，违反膜需要全身麻醉。而且，任何 涉及手术的治疗很昂贵，在世界各地不实用，导致听力损失和 许多发展中国家中耳炎导致的死亡。为了增强中耳疾病的医学治疗， 我们使用顺序选择的噬菌体肽肽文库来识别跨越稀有的新型肽 鼓膜膜通过运输货物时的主动工艺。这些肽之一的噬菌体之一 进入中耳的106-7倍噬菌体率的速度为106-7倍。肽也越过膜 独立于噬菌体。我们通过扩展肽长度的延伸，确定的氨基酸进行了优化的递送 序列，与快速传输相关的基序，表明跨人鼓膜膜和 获得了有关运输机制的重要证据。但是，存在许多障碍 转化为临床用法。 Trans-TM肽运输的长期安全性和功效必须为 评估。应该开发一种长期交付的实用方法。肽介导的应用 应探索到大型药品包的运输。应该更好地理解运输机制。 是否有比在动物中发现的肽更有效的肽可以在人类TM上运输 模型应确定。最后，应确认在人类TM中的药物递送。这 拟议的研究将进一步发展一个完全新颖的范式来治疗中耳疾病。 倍跨药物的递送将达到较高的中耳药物水平，并避免侧或脱靶效应， 与系统性药物相比。该方法将为治疗提供广泛的应用 中耳炎和其他中耳状况。