Adenoviruses remain the most common cause of external eye infections worldwide. Rapid transmission at home, school, and at work lead to significant patient morbidity and economic losses. Progress toward controlling global epidemics and treating patients has been made with the development of our rabbit model and successful preclinical studies testing a promising new antiviral, cidofovir.
The specific aims are: 1) To determine the underlying molecular mechanisms of adenovirus resistance to the antiviral, cidofovir, and to define the consequences of such resistance on viral pathogenesis, 2) To identify the anatomical sites of adenoviral replication following topical infection of the rabbit eye. The PI will determine if retrograde axoplasmic flow will transport adenovirus centrally to the ipsilateral trigeminal ganglion. If so, it will establish the use of adenovirus in our model as a possible neuronal gene delivery vector for gene therapy. 3) To determine if host cell binding specificity explains, in part, the epidemiological and experimental differences in oculotropism between select Group D adenoviruses (Ad8, Ad19, Ad37) and respiratropic Group C adenoviruses (Ad1, Ad2, Ad5, Ad6).
This aim will provide a better understanding of adenovirus infection at the cellular level with potential applications for new antiviral therapies based on receptor blockade and better host cell targeting in gene therapy, and 4) To assess whether there is a potential therapeutic role for topical anti-inflammatory and/or immunomodulatory agents as adjuncts to cidofovir antiviral therapy in the optimal treatment of adenoviral ocular infections using the rabbit model. In summary, the PI proposes new pathogenesis studies using cell culture, corneal organ culture and an animal model to better understand the underlying pathogenic mechanisms of ocular disease and the means by which it may be prevented and treated.
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