Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

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.

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Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration

The Journal of Pathology ◽

10.1002/path.4128 ◽

2013 ◽

Vol 229 (5) ◽

pp. 729-742 ◽

Cited By ~ 72

Author(s):

Katayoon B Ebrahimi ◽

Natalia Fijalkowski ◽

Marisol Cano ◽

James T Handa

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Retinal Pigmented Epithelium ◽

Age Related ◽

Pigmented Epithelium ◽

Complement Regulators

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

PLoS ONE ◽

10.1371/journal.pone.0173575 ◽

2017 ◽

Vol 12 (3) ◽

pp. e0173575 ◽

Cited By ~ 11

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

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NADPH Oxidase Activity in Retinal Pigmented Epithelium as a Target for Prevention of Age-related Macular Degeneration

Medical Research Archives ◽

10.18103/mra.v5i1.944 ◽

2017 ◽

Vol 5 (1) ◽

Author(s):

Mark McCarty

Keyword(s):

Nadph Oxidase ◽

Macular Degeneration ◽

Oxidase Activity ◽

Age Related Macular Degeneration ◽

Retinal Pigmented Epithelium ◽

Nadph Oxidase Activity ◽

Age Related ◽

Pigmented Epithelium

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Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2021-000774 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000774

Author(s):

Minwei Wang ◽

Shiqi Su ◽

Shaoyun Jiang ◽

Xinghuai Sun ◽

Jiantao Wang

Keyword(s):

Mitochondrial Dysfunction ◽

Macular Degeneration ◽

Vision Loss ◽

Cell Structure ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Amyloid Β ◽

Age Related Macular Degeneration ◽

Amyloid Β Peptide ◽

Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05025-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yamin Li ◽

Lina Liang ◽

Torkel Snellingen ◽

Kai Xu ◽

Yun Gao ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Macular Degeneration ◽

Vision Loss ◽

Age Related Macular Degeneration ◽

Case Report Form ◽

Link Type ◽

Anti Vegf ◽

Age Related ◽

Function Test

Abstract Background Neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness among the older people aged 50 and over. Although anti-vascular endothelial growth factor (anti-VEGF) therapies have resulted in improving patient outcomes, there are limitations associated with these treatments. In China, traditional Chinese medicine (TCM) has been used to treat eye diseases for more than 2000 years. Previous studies have shown that TCM may be beneficial for nAMD patients. However, explicit evidence has not been obtained. The purpose of the present trial is to examine the efficacy and safety of the Mingjing granule, a compound Chinese herbal medicine, for nAMD patients. Methods/design This is a double-blind, placebo-controlled, randomized trial of Mingjing granule as an add-on to intravitreous ranibizumab for nAMD. One hundred eighty nAMD patients from six hospitals in China will be enrolled according to the inclusion and exclusion criteria and randomly allocated into two groups, 90 in each. All participants will receive a 24-week treatment and then be followed up for another 24 weeks. The primary outcome is the mean change of best-corrected visual acuity at week 24 and 48 as compared to the baseline. The secondary outcomes include mean change in central retinal thickness, area of retinal hemorrhage and exudation, and TCM syndrome score, mean number of intravitreal ranibizumab injection, and total cost of the treatment. Indexes of safety include blood regular test, urine regular test, liver function test, renal function test, and electrocardiogram from baseline to weeks 24 and 48. Qualitative control and some standard operating processes will be formed throughout the trial. Any ocular or systemic adverse events will be treated suitably, and related data will be recorded accurately and completely in the case report form. Discussion Based on previous empirical and animal laboratory studies, this study will address the question of whether Mingjing granule could contribute to improving efficacy, safety, and efficiency with need for fewer intravitreal injections of anti-VEGF, improving compliance and visual outcomes in the management of persons with nAMD. Trial registration Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR2000035990. Registered on 21 August 2020.

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Introduction to the multi-author review on macular degeneration

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03418-5 ◽

2020 ◽

Vol 77 (5) ◽

pp. 779-780 ◽

Cited By ~ 1

Author(s):

Anu Kauppinen

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

The Elderly ◽

Developed Countries ◽

Age Related Macular Degeneration ◽

Age Related ◽

Severe Vision Loss ◽

Author Review ◽

Dry Amd ◽

Endothelial Growth Factor

AbstractProlonged life expectancies contribute to the increasing prevalence of age-related macular degeneration (AMD) that is already the leading cause of severe vision loss among the elderly in developed countries. In dry AMD, the disease culminates into vast retinal atrophy, whereas the wet form is characterized by retinal edema and sudden vision loss due to neovascularization originating from the choroid beneath the Bruch’s membrane. There is no treatment for dry AMD and despite intravitreal injections of anti-vascular endothelial growth factor (VEGF) that suppress the neovessel formation, also wet AMD needs new therapies to prevent the disease progression and to serve patients lacking of positive response to current medicines. Knowledge on disease mechanisms is a prerequisite for the drug development, which is hindered by the multifactorial nature of AMD. Numerous distinguished publications have revealed AMD mechanisms at the cellular and molecular level and in this multi-author review, we take a bit broader look at the topic with some novel aspects.

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Long-term outcome of neovascular age-related macular degeneration: association between treatment outcome and major risk alleles

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319054 ◽

2021 ◽

pp. bjophthalmol-2021-319054

Author(s):

Brice Nguedia Vofo ◽

Gala Beykin ◽

Jaime Levy ◽

Itay Chowers

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Age Related Macular Degeneration ◽

Long Term Outcome ◽

Risk Alleles ◽

Macular Atrophy ◽

Anti Vegf ◽

Age Related

AimsTo evaluate the long-term functional and anatomical outcomes of neovascular age-related macular degeneration (nvAMD) treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) for up to 10 years, and to identify associated risk factors.MethodsClinical and optical coherence tomography findings were retrieved for nvAMD cases treated with intravitreal anti-VEGF compounds using a treat-and-extend protocol. In addition, the major risk alleles for AMD in the CFH (rs1061170), HTRA1 (rs1200638) and C3 (rs2230199) genes were genotyped.ResultsFrom 276 eligible eyes in 206 patients, 80 eyes (29%) in 66 patients (32.0%) had a follow-up period of ≥8 years and were included in this study. Over a 10-year period, 73.3±28.0 (mean±SD) anti-VEGF injections were administered. Best-corrected visual acuity (BCVA; LogMAR) deteriorated from 0.55±0.53 at baseline to 1.00±0.73 at 10 years (p<0.0005). Central subfield thickness (CST) decreased from 415.8±162.1 µm at baseline to 323±113.6 µm (p<0.0005) after three monthly injections and remained lower than baseline throughout the follow-up period. Visual outcome was associated with BCVA and intraretinal fluid (IRF) at baseline, macular atrophy, and macular thinning at follow-up. The decrease in CST was inversely correlated with the number of CFH and/or C3 risk alleles carried by the patient (Pearson’s r: −0.608; p=0.003).ConclusionsPatients with nvAMD who received anti-VEGF therapy for 10 years developed substantial vision loss associated with the presence of IRF at baseline and macular atrophy. Major risk alleles for AMD in two complement genes were associated with a reduced long-term reduction in macular thickness.

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