Repurposing Fluoxetine for Macular Degeneration

Meenakshi Ambati

Overview

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 years of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon, amyloid β deposition, and iron overload. Alu RNA, amyloid β, and iron induce RPE degeneration by activating the NLRP3-ASC inflammasome. I report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in a computational molecular model and provide biochemical confirmation of this binding in vitro and in cells. I also show that fluoxetine inhibits NLRP3 ATPase activity as well as assembly and activation of the NLRP3-ASC inflammasome in RPE cells and macrophages, two critical cell types in dry AMD. Further, I demonstrate, in tissue-based studies, that fluoxetine, unlike several other anti depressant drugs, reduces RPE degeneration induced by Alu RNA, amyloid β, and iron. Finally, by bioinformatic analysis of 3 health insurance databases comprising more than 130 million Americans, I report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies triangulate to link fluoxetine as a potential drug repurposing candidate for a major unmet medical need that causes blindness in millions of people in the United States and across the world.

From the student

Vision is, arguably, our most important special sense. An enormous portion of our brain activity is designed to process visual information. After performing research for a school project, I was astonished that there is a plethora of diseases that affect our vision, many of which have no cure. Specifically, I learned of a disease called Dry Macular Degeneration that affects 200 million people yet has no FDA-approved treatment. The thought that millions of people were suffering from blindness was too much to bear. I could not imagine a life where I could not see my loved ones or experience life the way most do. Therefore, I started reading scientific literature on macular degeneration, determined to find a sliver of hope that scientists would be making breakthroughs in finding a remedy. I was taken aback to learn that more than a hundred clinical trials had been conducted but none succeeded. Despite decades of research and development costing billions of dollars, dry macular degeneration remains an unsolved problem. I believed that there had to be a way to expedite the clinical trial process in order to discover an effective treatment for patients as soon as possible. So, I resolved to perform research on this debilitating disease and contribute to the search for a therapy. Pursuing science in a research lab had been a dream of mine for several years, and I was incredibly grateful to find a mentor who studied dry macular degeneration and was willing to foster my growth as a scientist as well as educating me on how to work in a lab.