scholarly journals Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity

2021 ◽  
Vol 7 (40) ◽  
Author(s):  
Shinichi Fukuda ◽  
Siddharth Narendran ◽  
Akhil Varshney ◽  
Yosuke Nagasaka ◽  
Shao-bin Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Macular Degeneration ◽  
Retinal Pigmented Epithelium ◽  
Complementary Dna ◽  
Pigmented Epithelium

scholarly journals Identification of Fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

2021 ◽  
Author(s):  
Meenakshi Ambati ◽  
Ivana Apicella ◽  
Siddharth Narendran ◽  
Shao-bin Wang ◽  
Hannah Leung ◽  
...  
Keyword(s):  
Health Insurance ◽  
Macular Degeneration ◽  
The United States ◽  
Clinical Depression ◽  
Age Related Macular Degeneration ◽  
Retinal Pigmented Epithelium ◽  
Rpe Cells ◽  
Age Related ◽  
Pigmented Epithelium ◽  
Dry Amd

AbstractThe atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no 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 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 that it inhibits activation of the NLRP3-ASC inflammasome in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other anti-depressant 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 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.Significance StatementDry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no FDA-approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents the assembly and activation of the NLRP3-ASC inflammasome. As a result, it also blocks the degeneration of retinal pigmented epithelium (RPE) cells in an animal model of dry AMD. Furthermore, we demonstrate through an analysis of health insurance databases that use of this FDA-approved anti-depressant drug is associated with reduced incidence of dry AMD. These studies identify that fluoxetine is a potential repurposing candidate for AMD, a prevalent cause of blindness.

Secretory proteostasis of the retinal pigmented epithelium: Impairment links to age-related macular degeneration

2020 ◽  
Vol 79 ◽  
pp. 100859
Author(s):  
Luminita Paraoan ◽  
Umar Sharif ◽  
Emil Carlsson ◽  
Wasu Supharattanasitthi ◽  
Nur Musfirah Mahmud ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Retinal Pigmented Epithelium ◽  
Age Related ◽  
Pigmented Epithelium

scholarly journals In vitro differentiation of cGMP-grade retinal pigmented epithelium from human embryonic stem cells

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Fernando H. Lojudice ◽  
Rodrigo A. Brant Fernandes ◽  
Francesco Innocenti ◽  
Carlos E. Franciozi ◽  
Priscila Cristovam ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Macular Degeneration ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Age Related Macular Degeneration ◽  
World Health ◽  
Retinal Pigmented Epithelium ◽  
Rpe Cells ◽  
Pigmented Epithelium

Abstract Background The World Health Organization (WHO) estimates that the number of individuals who lose their vision due to retinal degeneration is expected to reach 6 million annually in 2020. The retinal degenerative diseases affect the macula, which is responsible for central and detailed vision. Most macular degeneration, i.e., age-related macular degeneration (AMD) develops in the elderly; however, certain hereditary diseases, such as the Stargardt disease, also affect young people. This degeneration begins with loss of retinal pigmented epithelium (RPE) due to formation of drusen (atrophic) or abnormal vessels (exudative). In wet AMD, numerous drugs are available to successful treat the disease; however, no proven therapy currently is available to treat dry AMD or Stargardt. Since its discovery, human embryonic stem cells (hESCs) have been considered a valuable therapeutic tool. Some evidence has shown that transplantation of RPEs differentiated from hESCs cells can result in recovery of both RPE and photoreceptors and prevent visual loss. Methods The human embryonic WA-09 stem cell lineage was cultured under current Good Manufacturing Practices (cGMP) conditions using serum-free media and supplements. The colonies were isolated manually and allowed to spontaneously differentiate into RPE cells. Results This simple and effective protocol required minimal manipulation and yielded more than 10e8 RPE cells by the end of the differentiation and enrichment processes, with cells exhibiting a cobblestone morphology and displaying cellular markers and a gene expression profile typical of mature RPE cells. Moreover, the differentiated cells displayed phagocytic activity and only a small percentage of the total cells remained positive for the Octamer-binding transcriptions factor 4 (OCT-4) pluripotency cell marker. Conclusions These results showed that functional RPE cells can be produced efficiently and suggested the possibility of scaling-up to aim at therapeutic protocols for retinal diseases associated with RPE degeneration.

scholarly journals Generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age related macular degeneration

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0173575 ◽  
Author(s):  
Zhouhui Geng ◽  
Patrick J. Walsh ◽  
Vincent Truong ◽  
Caitlin Hill ◽  
Mara Ebeling ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Retinal Pigmented Epithelium ◽  
Age Related ◽  
Pigmented Epithelium

scholarly journals EFFECTS OF CYCLIC AMP AND SEPHADEX FRACTIONS OF CHICK EMBRYO EXTRACT ON CLONED RETINAL PIGMENTED EPITHELIUM IN TISSUE CULTURE

1974 ◽  
Vol 61 (2) ◽  
pp. 369-382 ◽  
Author(s):  
D. A. Newsome ◽  
R. T. Fletcher ◽  
W. G. Robison ◽  
K. R. Kenyon ◽  
G. J. Chader
Keyword(s):  
Molecular Weight ◽  
Chick Embryo ◽  
Adenosine Monophosphate ◽  
Cell Number ◽  
Retinal Pigmented Epithelium ◽  
Culture Dish ◽  
Adhesive Properties ◽  
Embryo Extract ◽  
Chick Embryo Extract ◽  
Pigmented Epithelium

The effects of dibutyryl cyclic 3',5'-adenosine monophosphate (BcAMP) and Sephadex G-25 fractions of chick embryo extract on the growth rate, morphology, and pigmentation of normal chick retinal pigmented epithelium (PE) were investigated. Seven cloned PE cell lines were each grown in modified Ham's F-12 medium alone (F-12), or in F-12 supplemented with either high molecular weight (H) or low molecular weight (L) fractions of chick embryo extract. Cells grown in F-12 alone or in L medium formed compact epithelial sheets, whereas cells grown in H had a fibrocytic appearance and formed poorly organized monolayers. In H plus BcAMP, cell morphology was more epithelioid than in H alone, and generally the monolayers appeared more differentiated. Under each of these three culture conditions, 2 x 10-4 M BCAMP retarded the increase in cell number and decreased the final number of cells per culture dish, but had little effect on plating efficiency. BcAMP also increased the rate of cell adhesion to a plastic substratum. Pigmentation was marked in cultures grown in F-12 or in L alone, but the addition of BcAMP dramatically reduced visible pigmentation. This effect was reversed when BcAMP was removed from the culture medium. Thus BcAMP modifies cell and colonial morphology, rate of cell accumulation, adhesive properties, and pigmentation of normal PE cells.

Sign in / Sign up

Export Citation Format

Share Document