Dynasore Analogues for Ocular Surface Protection

7. PROJECT SUMMARY Diseases of the ocular surface are among the top reasons for visits to eye care practitioners. These conditions can severely affect eyesight and quality of life. Symptoms may include blurry vision, discomfort or pain, redness and itching, and in severe cases, blindness due to corneal scarring. Many ocular surface diseases are initiated by loss of tear film homeostasis and can be grouped under a syndrome known as dry eye. Tear dysfunction leading to desiccating stress, initiates an autoimmune-like “vicious cycle of inflammation” that damages the ocular surface barrier. The vicious cycle is recognized as the core driver of the pathologic process, leading to chronic dry eye disease. Anti-inflammatory steroids and small molecules targeting autoimmune T-cell function are currently the only Food and Drug Administration (FDA)-approved therapeutics. These drugs are not effective in all patients, take a long time to work, and have unpleasant side effects. Current opinion holds that breaking the inflammatory vicious cycle at alternative entry points is the key to new treatments. Direct protection of the ocular surface barrier could provide such a new entry point. This should relieve chronic dry eye by ramping down the inflammatory vicious cycle, like current therapeutics. However, because it represents a different entry point, it may be efficacious in chronic situations where current drugs do not work. A novel benefit is the potential for very rapid relief of eye irritation in situations where dry eye is exacerbated by environmental, and other factors. In a recent publication, the academic lab associated with this project reported the novel discovery that Dynasore and Dyngo-4A are remarkably protective of the ocular surface barrier. Dynasore and Dyngo-4A belong to a group of small molecules targeting dynamin family GTPases, which also protect cells and tissues against oxidative stress and reduce inflammatory cytokine production. The innovation of Dynasore analogues for dry eye is that they target ocular surface barrier damage. There are no such therapeutics available at this time that act at this point in the vicious cycle. The long-term goal of this project is development of a novel FDA-approved drug based on Dynasore compounds. This phase I program will proceed via three Specific Aims: 1) prepare a Dynasore analogue library to define structure-activity relationships; 2) test analogues for activity in a validated human cell culture model of the ocular surface; 3) provide proof-of-concept using a relevant mouse model for chronic dry eye. Following completion of this phase I effort, the team will have selected a lead compound as a potential treatment for ocular surface disease in dry eye. During phase II, additional compounds will be prepared to fine-tune efficacy and pharmacokinetic properties and animal testing will be expanded to examine toxicity or eye irritation, and look for systemic exposure. Finally, formulation and dosage will be fine-tuned to maximize efficacy, shelf life and ease of application, while decreasing any toxic or off target effects that may arise.8. PROJECT NARRATIVE Dry eye is a global problem, afflicting over 30 million people in the United States alone, and at least 344 million people worldwide. Prevalence is higher among women than men and increases with age, but is also notable among the 18-34-year age group. It has been estimated that the overall burden of dry eye for the US healthcare system is $3.84 billion. These facts underpin the great need for new treatments.