Treatment for chronic otitis media often involves surgery, including tympanostomy tubes which provide aeration and allow the penetration of topical medications through the tympanic membrane. Such local drug treatment has been found to be highly effective. However, surgery is expensive and in many parts of the world is not practical, leading to hearing loss and deaths due to otitis media in the developing world. To enhance medical treatment of middle ear disorders, we used sequential selection of phage-display peptide libraries to identify rare, novel peptides that actively cross the tympanic membrane while transporting cargo. Preliminary data indicate that a bacteriophage bearing one of these peptides enters the middle ear at 106 times the rate of an untargeted phage. We propose to extend this work by determining the rate and saturation level of transtympanic transport for all identified peptides. We will evaluate the external ear, tympanic membrane and middle ear after transtympanic peptide exposure, to determine whether there are any adverse effects, and assess the ability of peptides to carry drugs and to influence a middle ear infection. We will also determine whether these peptides cross the human tympanic membrane, and characterize the binding partners that mediate transtympanic transport. The proposed research will lead to 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

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 medications through the tympanic membrane. This 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 into the human middle ear. If successful, this project will establish an entirely novel therapeutic strategy for otitis media, on that will, for example, 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 #
5R01DC012595-02
Application #
8485577
Study Section
Special Emphasis Panel (ZDC1-SRB-Y (53))
Program Officer
Watson, Bracie
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$312,906
Indirect Cost
$111,031
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; 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
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
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
Hernandez, Michelle; Leichtle, Anke; Pak, Kwang et al. (2015) The transcriptome of a complete episode of acute otitis media. BMC Genomics 16:259
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
Kurabi, Arwa; Pak, Kwang; Dang, Xitong et al. (2013) Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. PLoS One 8:e61394
Chan, Elizabeth A W; Teng, Grace; Corbett, Elizabeth et al. (2013) Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2. Proc Natl Acad Sci U S A 110:E4628-37
Li, Jian-Dong; Hermansson, Ann; Ryan, Allen F et al. (2013) Panel 4: Recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models. Otolaryngol Head Neck Surg 148:E52-63