Targeting Inflammatory Caspases as a Novel Approach to Treat Neovascular Age-Related Macular Degeneration

Summary

The “wet” form of age-related macular degeneration results from a localized inflammation in the back of the eye that leads to vision loss due to abnormal blood vessel formation that impairs the ability to see. Findings from several research groups and our own have identified a particular protein complex, called the inflammasome, as being a likely contributor to this inflammation that promotes the manifestation of “wet” AMD. We have established a mouse model of this blinding eye disease and could show that inhibiting the inflammasome could strongly suppress the manifestation of “wet” AMD.In order to develop novel pharmacologic treatments for patients with “wet” AMD, it is important to understand which particular cell types in the eye are especially important for mediating the effects of the inflammasome, so that these specific cell types could be targeted selectively while reducing therapeutic side effects in other cell types.

Project Details

In this project I am trying to determine how a pro-inflammatory protein complex, called the inflammasome, contributes to the manifestation of neovascular AMD. The inflammasome is activated in AMD, but it is not known through which specific disease processes the inflammasome may promote AMD. It is also not known whether the involved proteins may inhibit AMD through inflammasome-independent activities. In this project I will utilize mouse genetic approaches with an innovative mouse model of AMD to conclusively determine how and to what extent the inflammasome contributes to the manifestation and progression of AMD pathologies. I will also determine whether inflammasome-dependent or inflammasome-independent activities of major components of this pro-inflammatory complex contribute to AMD.

The findings of this study will provide important insights into how the inflammasome promotes neovascular AMD. The experiments are expected to provide answers to key questions in the AMD field that may instruct novel treatment approaches. Current approaches to inhibit neovascular AMD have targeted the abnormal blood vessel formation, but these approaches are limited by unwanted side effects on normal blood vessels in the eye that are required for normal retinal function. In contrast, targeting inflammatory pathways and mediators in the eye is expected to only inhibit the disease process but not affect the normal tissues in the eyes of patients with AMD. Thus, the outcome of this project is likely to provide new therapeutic strategies in the treatment of neovascular AMD that selectively targets cell types involved in disease progression without affecting normal retinal cell types. These new treatment approaches may allow to inhibit AMD more efficiently without detrimental side effects on normal blood vessels that are required for the maintenance of normal
retinal function.