@article{4300408571434f76be2d911a0a3bf9d2,
title = "Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration",
abstract = "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 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.",
keywords = "Fluoxetine, Health insurance databases, Macular degeneration, Molecular modeling, Retina",
author = "Meenakshi Ambati and Ivana Apicella and Wang, {Shao Bin} and Siddharth Narendran and Hannah Leung and Felipe Pereira and Yosuke Nagasaka and Peirong Huang and Akhil Varshney and Baker, {Kirstie L.} and Marion, {Kenneth M.} and Mehrdad Shadmehr and Stains, {Cliff I.} and Werner, {Brian C.} and Sadda, {Srinivas R.} and Taylor, {Ethan W.} and Sutton, {S. Scott} and Joseph Magagnoli and Gelfand, {Bradley D.}",
note = "Funding Information: Author contributions: M.A., I.A., S.-b.W., S.N., Y.N., P.H., B.C.W., J.M., and B.D.G. designed research; M.A., I.A., S.-b.W., S.N., H.L., F.P., Y.N., P.H., A.V., K.L.B., K.M.M., M.S., C.I.S., B.C.W., S.R.S., E.W.T., S.S.S., and J.M. performed research; M.A., I.A., S.-b.W., S.N., H.L., F.P., Y.N., P.H., A.V., K.L.B., K.M.M., M.S., C.I.S., B.C.W., S.R.S., E.W.T., S.S.S., J.M., and B.D.G. analyzed data; and M.A., I.A., S.-b.W., S.N., E.W.T., and B.D.G. wrote the paper. Competing interest statement: M.A., B.D.G., S.N., S.-b.W., I.A., and F.P. are named as inventors on patent applications on macular degeneration filed by the University of Virginia. S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics unrelated to this work. S.R.S. has been a consultant for 4DMT, Allergan, Amgen, Centervue, Heidelberg, Roche/Genentech, Novartis, Optos, Regeneron, and Thrombogenics and has received research funding from Carl Zeiss Meditec, all unrelated to this work. B.D.G. is a co-founder of DiceRx. This article is a PNAS Direct Submission. J.O.L. is a guest editor invited by the Editorial Board. Funding Information: ACKNOWLEDGMENTS. We thank D. Robertson, G. Pattison, J. Hu, and K.A. Fox for their technical assistance. This work was funded, in part, by the University of Virginia Strategic Investment Fund. B.D.G. has received support from NIH grants (R01EY028027, R01EY031039, and R01EY032512), BrightFocus Foundation, and the Owens Family Foundation. C.I.S. received support from the NIH (R35GM119751) and the University of Virginia. The FP7 WeNMR (Project No. 261572), H2020 West-Life (Project No. 675858), and the European Open Science Cloud Hub (Project No. 777536) European e-Infrastructure projects are acknowledged for the use of their web portals, which make use of the European Grid Infrastructure with the dedicated support of CESNET-MetaCloud, Italian Institute of Nuclear Physics Padova, NCG-INGRID-PT, Taiwan National Center for High-performance Computing, SURFsara, and Dutch National Institute for Subatomic Physics and the additional support of the national Grid Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, United Kingdom, Taiwan, and the US Open Science Grid. The content of this article is solely our responsibility and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = oct,
day = "12",
doi = "10.1073/pnas.2102975118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "41",
}