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.

Public Health Relevance

Relevance to Public Health: This translational research project seeks to improve the treatment of otitis media and other disorders of the middle ear, by developing methods for active delivery of therapies through the intact tympanic membrane. The project will build upon our recent discovery of rare peptides that can rapidly transit the tympanic membrane while attached to bacteriophage, to develop carriers that can actively transport drugs, drug packages and gene therapy into the human middle ear. If successful, this project will establish an entirely novel local delivery therapeutic strategy for otitis media and other middle ear disorders without the need for anesthesia in children while preserving the tympanic membrane integrity and structure, and will avoid systemic side effects and exposure of off-target bacteria to antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC012595-06
Application #
9728397
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Watson, Bracie
Project Start
2012-07-01
Project End
2024-02-28
Budget Start
2019-03-08
Budget End
2020-02-29
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kurabi, Arwa; Schaerer, Daniel; Chang, Lisa et al. (2018) Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study. J Drug Target 26:127-134
Deniffel, Dominik; Nuyen, Brian; Pak, Kwang et al. (2017) Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice. Infect Immun 85:
Kurabi, Arwa; Pak, Kwang; Ryan, Allen F et al. (2016) Innate Immunity: Orchestrating Inflammation and Resolution of Otitis Media. Curr Allergy Asthma Rep 16:6
Cho, Chang Gun; Pak, Kwang; Webster, Nicholas et al. (2016) Both canonical and non-canonical NF-?B activation contribute to the proliferative response of the middle ear mucosa during bacterial infection. Innate Immun 22:626-634
Kurabi, Arwa; Pak, Kwang K; Bernhardt, Marlen et al. (2016) Discovery of a Biological Mechanism of Active Transport through the Tympanic Membrane to the Middle Ear. Sci Rep 6:22663
Harrop-Jones, Anne; Wang, Xiaobo; Fernandez, Rayne et al. (2016) The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss. Audiol Neurootol 21:12-21
Hernandez, Michelle; Leichtle, Anke; Pak, Kwang et al. (2015) The transcriptome of a complete episode of acute otitis media. BMC Genomics 16:259
Leichtle, Anke; Klenke, Christin; Ebmeyer, Joerg et al. (2015) NOD-Like Receptor Signaling in Cholesteatoma. Biomed Res Int 2015:408169
Kurabi, Arwa; Lee, Jasmine; Wong, Chelsea et al. (2015) The inflammasome adaptor ASC contributes to multiple innate immune processes in the resolution of otitis media. Innate Immun 21:203-14
Suzukawa, Keigo; Tomlin, Julia; Pak, Kwang et al. (2014) A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation. PLoS One 9:e102739

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