SBIR-STTR Award

Otitis media with effusion (OME) is one of the most prevalent inflammatory diseases in the pediatric population, and is associated with pain and hearing loss. OME is characterized by release of inflammatory mediators and enzymes such as pro-inflammatory cytokines, cellular infiltration into the middle ear, and secretion of a mucin-rich effusion. In the majority of cases, inflammation and resulting fluid accumulation are initially triggered by stimulation of host immune cells with specific bacterial products, such as end toxin. These stimulatory products are found both on intact viable bacteria and bacterial debris that is present after bacterial death. Currently, antibiotics are used almost exclusively for treatment of otiUs media, however antibiotic therapy only kills the bacteria and does not specifically target the inflammation and accumulation of fluid in the middle ear that irresponsible for the pain and diminished hearing seen in OME. The goal of this proposal will be to test the feasibility of a novel therapy to minimize or resolve the inflammation and result in accumulation of middle ear fluid, and prevent the hearing loss in OME. Our strategy will be to block at the initiating stage the intracellular activation that results from the interaction of bacterial products with host immune cells within the middle ear leading to inflammation and the clinical complications of OME. This proposal will establish conditions for inhibiting the cellular activation and inflammation induced both by specific bacterial products and cell extracts from killed whole bacteria. Once these conditions have been defined in vitro (Specific aim #1), the in vivo effectiveness of this therapeutic approach to minimize inflammation will be examined by assessing middle ear pathology, middle ear fluid accumulation, and prevention of hearing loss in an in vivo model of OME induced by injection of viable bacteria (specific aim #2). We speculates that the most efficient management of OME will involve a combination of antibiotics and a treatment specific for bacterial-induced inflammation.

Thesaurus Terms:
antiinfective agent, antiinflammatory agent, drug design /synthesis /production, host organism interaction, inflammation, otitis media bacteria infection mechanism, fluid laboratory mouse, laryngoscopy

Bacterial infections are the primary cause of otitis media with effusion (OME), an inflammatory disease of the middle ear. OME is characterized by production of pro-inflammatory cytokines within the middle ear and development of inflammation and fluid accumulation. While the primary treatment for OME is antibiotics, there is no therapy that directly targets the inflammation and fluid accumulation. This Phase II proposal will provide pre-clinical assessment of a therapy to treat bacterial-induced inflammation. Targeted Gene Delivery has developed a novel peptide drug that specifically blocks the intracellular signaling and cell activation (production of pro-inflammatory cytokines) that results from the interaction of bacteria and immune cells. Preliminary in vivo studies demonstrated a significant anti-inflammatory effect in a mouse model of bacterial induced OME, with marked reduction in fluid accumulation, number of inflammatory cells, and mucosal thickening in the middle ear. In the current study, experiments will test the efficacy of this therapy in reducing inflammation in a mouse model of bacterial-induced OME and the impact of this novel therapy on improving hearing thresholds. These studies have the potential to define a new approach to treating bacterial-induced inflammation that will have application in OME and a variety of other inflammatory diseases.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
Antiinfective Agent, Antiinflammatory Agent, Drug Design /Synthesis /Production, Drug Screening /Evaluation, Ear Infection, Host Organism Interaction, Inflammation, Microorganism Disease Chemotherapy, Nonhuman Therapy Evaluation, Otitis Media Bacteria Infection Mechanism, Fluid, Gram Negative Bacteria, Gram Positive Bacteria Laboratory Mouse