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.

摘要