Targeting Inflammatory Caspases as a Novel Approach to Treat Neovascular Age-Related Macular Degeneration
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.
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
About the Researcher
I am an Associate Professor at Harvard Medical School and Massachusetts General Hospital (MGH). I have a very active laboratory at MGH, where I also see patients. I am originally from Germany, where I obtained my MD from the University of Cologne. I obtained my PhD training as well as my postdoctoral training at Harvard Medical School, followed by residency training at Columbia University. I started my laboratory at MGH after my residency, supported by funding for AMD research from the NEI. I have a more than 20-year track record on utilizing novel genetic mouse models to elucidate the pathomechanisms in AMD. As a graduate student I identified a novel genetic mouse model that develops key clinical findings of dry AMD. During my postdoctoral training I could show that the growth factor VEGF-A is essential for the development and maintenance of the choroidal vasculature. Moreover, I could show that peptides with anti-angiogenic activities could inhibit AMD in mouse models. In my own laboratory, we identified a genetic mouse model that develops key aspects of human neovascular AMD. We utilized this mouse model to investigate the pathomechanisms that lead to neovascular AMD pathologies. We uncovered a critical role of the inflammasome for the manifestation of AMD, thereby demonstrating that the inflammasome activation that has been observed in human AMD is not just a disease marker, but actually contributes to the disease process that could be targeted therapeutically. Our work has provided a much more detailed understanding of how specific inflammasome components promote AMD in vivo.
I hope that my laboratory can bring a fresh and unbiased perspective to the field of AMD research that may yield unexpected findings in our understanding of AMD disease mechanisms. As a graduate student I have worked in a laboratory at Harvard Medical School that focused on extracellular matrix research with no expertise in eye research. While working on a novel collagen, I unexpectedly discovered that mutant mice lacking this novel collagen developed dry AMD-like eye pathologies, and ever since I have focused on AMD research. I believe approaching eye diseases from a scientific background other than Ophthalmology enables an out-of-the-box unbiased perspective on important questions in the field. Similarly, I have been surrounded during my postdoctoral training, my clinical training and my current laboratory experience by scientists and clinicians from other research backgrounds and fields who are not Ophthalmologists or eye researchers. This diverse research background allows us to look at unanswered problems in AMD research from a different angle.
First published on: July 2, 2019
Last modified on: July 3, 2019