Treatment Of Age-related Macular Degeneration Research Articles

The UK clinical eye research strategy: refreshing research priorities for clinical eye research in the UK.

To validate and update the 2013 James Lind Alliance (JLA) Sight Lossand Vision Priority Setting Partnership (PSP)'s research priorities for Ophthalmology, as part of the UK Clinical Eye Research Strategy. Twelve ophthalmology research themes were identified from the JLA report. They were allocated to five Clinical Study Groups of diverse stakeholders who reviewed the top 10 research priorities for each theme. Using an online survey (April 2021-February 2023), respondentswere invited to complete one or more of nine subspecialty surveys. Respondents indicated which of the research questions they considered important and subsequently ranked them. In total, 2240 people responded to the survey (mean age, 59.3 years), from across the UK. 68.1% were female. 68.2% were patients, 22.3% healthcare professionals or vision researchers, 7.1% carers, and 2.1% were charity support workers. Highest ranked questions by subspecialty: Cataract (prevention), Cornea (improving microbial keratitis treatment), Optometric (impact of integration of ophthalmic primary and secondary care via community optometric care pathways), Refractive (factors influencing development and/or progression of refractive error), Childhood onset (improving early detection of visual disorders), Glaucoma (effective and improved treatments), Neuro-ophthalmology (improvements in prevention, diagnosis and treatment of neurodegeneration affecting vision), Retina (improving prevention, diagnosis and treatment of dry age-related macular degeneration), Uveitis (effective treatments for ocular and orbital inflammatory diseases). A decade after the initial PSP, the results refocus the most important research questions for each subspecialty, and prime targeted research proposals within Ophthalmology, a chronically underfunded specialty given the substantial burden of disability caused by eye disease.

Comparative study on the efficacy of Conbercept and Aflibercept in the treatment of neovascular age-related macular degeneration

This study compares the effectiveness of Conbercept and Aflibercept in treating neovascular age-related macular degeneration (nAMD). Conducted at the First Affiliated Hospital of Chongqing Medical University's Ophthalmology Department (May 2020–May 2023), this prospective study enrolled 159 nAMD patients. Participants were randomly divided into two groups: one receiving 0.5 mg Conbercept and the other 2 mg Aflibercept intravitreal injections. Over 12 months, the study, employing a Treat-and-Extend (T&E) regimen, assessed Best-Corrected Visual Acuity (BCVA), Central Retinal Thickness (CRT) changes and injection frequency. Of the 159 patients, 137 (149 eyes) completed the study. No significant age difference was found between the groups (P = 0.331). After 12 months, BCVA improved similarly in both groups (Conbercept: 52.8 ± 18.9, Aflibercept: 52.0 ± 19.7 letters; P = 0.820). CRT reduction was also comparable (Conbercept: 246.3 ± 82.8 µm, Aflibercept: 275.9 ± 114.3 µm; P = 0.079). Injection frequencies averaged 6.9 ± 0.7 (Conbercept) and 6.7 ± 0.7 (Aflibercept; P = 0.255). Subtype analysis revealed Type 1 MNV had higher baseline BCVA and lower CRT, with more frequent injections compared to other types. Both Conbercept and Aflibercept are clinically similar in efficacy for nAMD, with the T&E regimen proving therapeutically effective and potentially reducing patient costs. Anti-VEGF treatment efficacy varies across nAMD subtypes, indicating a potential benefit in tailored treatments for specific subtypes.Clinical trial registration number NCT05539235 (Protocol Registration and Results System).

Novel therapeutic perspectives for wet age-related macular degeneration: RGD-modified liposomes loaded with 2-deoxy-D-glucose as a promising nanomedicine

Choroidal neovascularization (CNV), characterized as a prominent feature of wet age-related macular degeneration (AMD), is a primary contributor to visual impairment and severe vision loss globally, while the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells is dictated by angiogenic growth factors alone. Even though treatments targeting vascular endothelial growth factor (VEGF), like Ranibizumab, are widely administered, more than half of the patients still exhibit inadequate or null responses, emphasizing the imperative need for solutions to this problem. Here, aiming to explore therapeutic strategies from a novel perspective of endothelial cell metabolism, a biocompatible nanomedicine delivery system is constructed by loading RGD peptide-modified liposomes with 2-deoxy-D-glucose (RGD@LP-2-DG). RGD@LP-2-DG displayed good targeting performance towards endothelial cells and excellent in vitro and in vivo inhibitory effects on neovascularization were demonstrated. Moreover, our mechanistic studies revealed that 2-DG interfered with N-glycosylation, leading to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling. Notably, the remarkable inhibitory effect on neovascularization and biocompatibility of RGD@LP-2-DG render it a highly promising and clinically translatable therapeutic candidate for the treatment of wet AMD and other angiogenic diseases, particularly in patients who are unresponsive to currently available treatments.

Potential application of traditional Chinese medicine in age-related macular degeneration—focusing on mitophagy

Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have shown that mitophagy, a highly specialized cellular degradation system, is implicated in the pathogenesis of AMD. Mitophagy selectively eliminates impaired or non-functioning mitochondria via several pathways, such as the phosphatase and tensin homolog-induced kinase 1/Parkin, BCL2-interacting protein 3 and NIP3-like protein X, FUN14 domain-containing 1, and AMP-activated protein kinase pathways. This has a major impact on the maintenance of mitochondrial homeostasis. Therefore, the regulation of mitophagy could be a promising therapeutic strategy for AMD. Traditional Chinese medicine (TCM) uses natural products that could potentially prevent and treat various diseases, such as AMD. This review aims to summarize recent findings on mitophagy regulation pathways and the latest progress in AMD treatment targeting mitophagy, emphasizing methods involving TCM.

Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

A systematic literature review on the pharmacological applications of the carotenoid norbixin

Carotenoids play essential roles in human health and can fight and prevent diseases. One carotenoid that is currently attracting scientific interest, particularly for its antioxidant properties, is norbixin. Studies related to its use in the treatment of diseases have become increasingly present in the medical field. This systematic literature review aimed to investigate and gather studies on the pharmacological activity of norbixin for health benefits and the treatment of diseases. Four databases were consulted: Web of Science, PubMed, Scopus, and ScienceDirect. Articles were extracted using a combination of keywords such as 'norbixin', 'antioxidant', 'diseases', 'in vitro', 'in vivo', etc. A total of 173 articles were identified. After applying the inclusion and exclusion criteria, 21 were selected for inclusion in this review. Studies have shown that norbixin, alone or in combination with other treatments, may be effective in DNA protection, tissue engineering, bone repair, and the prevention and treatment of age-related macular degeneration and cardiovascular disease. These results provide a solid basis for further studies aimed at exploring the pharmacological properties of norbixin and enabling its use in therapeutic applications.

Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

Complement regulation in the eye: implications for age-related macular degeneration.

Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.

Real-World Outcomes of Faricimab Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema

Real-World Outcomes of Faricimab Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema

Patient Experience Survey Of Anti-VEGF Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema.

Understanding patient perspectives of treatment may improve adherence and outcomes. This study explored real-world patient experiences with anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD). This multinational, non-interventional, quantitative, cross-sectional, observational survey assessed treatment barriers/burden, patient-reported visual functioning, and treatment satisfaction in DME and nAMD patients in the United States, United Kingdom, Canada, France, Italy, and Spain. Treatment patterns and visual outcomes were extracted from medical charts. Regression models evaluated relationships between adherence, total missed visits, number of anti-VEGF injections and clinical and patient-reported outcomes for visual functioning. Association between treatment satisfaction and aspects of burden were assessed. The survey was completed by 183 DME and 391 nAMD patients. Patients had moderately high vision-related functioning (25-item National Eye Institute Visual Functioning Questionnaire score: mean=74.8) and were satisfied with their current treatment (mean total score: Macular Disease Treatment Satisfaction Questionnaire=59.2; Retinopathy Treatment Satisfaction Questionnaire=61.3). Treatment satisfaction scores were worse with higher time-related impacts of treatment (nAMD/DME), higher impacts on finances and daily life (nAMD), negative impact on employment and lower expectations for treatment effectiveness (DME). Most patients reported ≥1 barrier (66.1% DME, 49.2% nAMD patients) related to treatment (35.0%), clinic (32.6%), and COVID-19 (21.1%). Moreover, 44.9% of patients reported some impairment in activities of daily living. Work absenteeism was observed among >60% of working patients. Nearly one-quarter (24.2%) of patients needed ≥1 day to recover from intravitreal injections; most reported ≥30 minutes of travel time (73.7%) and clinic wait time (54.2%). In unadjusted univariable analyses, treatment adherence (vs non adherence) was related to higher most recent visual acuity (β = 8.98 letters; CI, 1.34-16.62) and lower odds of visual acuity below driving vision (≤ 69 letters) (OR = 0.50; CI, 0.25-1.00) . More durable treatments with reduced frequency of injections/visits may reduce treatment burden and improve patient satisfaction, which may enhance adherence and visual outcomes.

RNA-sequencing expression profile and functional analysis of retinal pigment epithelium in atrophic age-related macular degeneration.

The retinal pigment epithelium (RPE) is fundamental to sustaining retinal homeostasis. RPE abnormality leads to visual defects and blindness, including age-related macular degeneration (AMD). Although breakthroughs have been made in the treatment of neovascular AMD, effective intervention for atrophic AMD is largely absent. The inadequate knowledge of RPE pathology is hindered by a lack of patient RPE datasets, especially at the single-cell resolution. In this study, we delved into a large-scale single-cell resource of AMD donors in which RPE cells were occupied in a substantial proportion. Bulk RNA-seq datasets of atrophic AMD were integrated to extract molecular characteristics of RPE in the pathogenesis of atrophic AMD. Both in vivo and in vitro models revealed that carboxypeptidase X, M14 family member 2 (CPXM2) was specifically expressed in the RPE cells of atrophic AMD, which might be induced by oxidative stress and involved in the epithelial-mesenchymal transition of RPE cells. Additionally, silencing of CPXM2 inhibited the mesenchymal phenotype of RPE cells in an oxidative stress cell model. Thus, our results demonstrate that CPXM2 plays a crucial role in regulating atrophic AMD and may serve as a potential therapeutic target for atrophic AMD.

Analysis of Choriocapillaris Reperfusion Topography following Faricimab Treatment for Neovascular Age-Related Macular Degeneration in Non-Treatment-Naïve Patients.

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; p = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; p = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression.

Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration

Most neovascular age-related macular degeneration (nAMD) treatments involve long-term follow-up of disease activity. Home-monitoring would reduce the burden on patients and their caregivers and release clinic capacity. To evaluate 3 vision home-monitoring tests for patients to use to detect active nAMD compared with diagnosing active nAMD at hospital follow-up during the after-treatment monitoring phase. This was a diagnostic test accuracy study wherein the reference standard was detection of active nAMD by an ophthalmologist at hospital follow-up. The 3 home-monitoring tests evaluated included the following: (1) the KeepSight Journal (KSJ [International Macular and Retinal Foundation]), which contains paper-based near-vision tests presented as word puzzles, (2) the MyVisionTrack (mVT [Genentech]) vision-monitoring mobile app, viewed on an Apple mobile operating system-based device, and (3) the MultiBit (MBT [Visumetrics]) app, viewed on an Apple mobile operating system-based device. Participants were asked to test weekly; mVT and MBT scores were transmitted automatically, and KSJ scores were returned to the research office every 6 months. Raw scores between hospital follow-ups were summarized as averages. Patients were recruited from 6 UK hospital eye clinics and were 50 years and older with at least 1 eye first treated for active nAMD for at least 6 months or longer to a maximum of 42 months before approach. Participants were stratified by time since starting treatment. Study data were analyzed from May to September 2021. The KSJ, mVT, and MBT were compared with the reference standard (in-hospital ophthalmologist examination). Estimated area under receiver operating characteristic curve (AUROC). The study had 90% power to detect a difference of 0.06, or 80% power to detect a difference of 0.05, if the AUROC for 2 tests was 0.75. A total of 297 patients (mean [SD] age, 74.9 [6.6] years; 174 female [58.6%]) were included in the study. At least 1 hospital follow-up was available for 312 study eyes in 259 participants (1549 complete visits). Median (IQR) home-monitoring testing frequency was 3 (1-4) times per month. Estimated AUROC was less than 0.6 for all home-monitoring tests, and only the KSJ summary score was associated with lesion activity (odds ratio, 3.48; 95% CI, 1.09-11.13; P = .04). Results suggest that no home-monitoring vision test evaluated provided satisfactory diagnostic accuracy to identify active nAMD diagnosed in hospital eye service follow-up clinics. Implementing any of these evaluated tests, with ophthalmologists only reviewing test positives, would mean most active lesions were missed, risking unnecessary sight loss.

Exploring Current Molecular Targets in the Treatment of Neovascular Age-Related Macular Degeneration toward the Perspective of Long-Term Agents.

Long-lasting anti-vascular endothelial growth factor (anti-VEGF) agents have become an option to reduce treatment frequency, with ongoing research exploring optimal responses and safety profiles. This review delves into molecular targets, pharmacological aspects, and strategies for achieving effective and enduring disease control in neovascular age-related macular degeneration (AMD). The molecular pathways involved in macular neovascularization, including angiogenesis and arteriogenesis, are explored. VEGF, PlGF, Ang-1, and Ang-2 play crucial roles in regulating angiogenesis, influencing vessel growth, maturation, and stability. The complex interplay of these factors, along with growth factors like TGFβ and bFGF, contributes to the pathogenesis of neovascular membranes. Current anti-VEGF therapies, including bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab, are discussed with a focus on their pharmacokinetics and clinical applications. Strategies to achieve sustained disease control in AMD involve smaller molecules, increased drug dosages, and novel formulations. This narrative review provides a comprehensive overview of the molecular targets and pharmacological aspects of neovascular AMD treatment.

Influence of submacular hemorrhage at baseline on the long-term outcomes of aflibercept treatment for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

To investigate the influence of submacular hemorrhage (SMH) at baseline on long-term visual outcomes of patients with typical age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV) treated with intravitreal aflibercept (IVA). In this retrospective study, eyes of treatment-naïve patients with tAMD and PCV who initiated IVA under a treat-and-extend regimen and were followed up for ≥ 5years were classified into the tAMD-SMH ( +), tAMD-SMH (-), PCV-SMH ( +), and PCV-SMH (-) groups based on the presence of SMH at baseline. Best-corrected visual acuity (BCVA) changes and macular fibrosis and atrophy incidences were assessed. This study included 127 eyes (127 patients), including 51 with tAMD and 76 with PCV; 18 eyes had SMH at baseline. In the tAMD-SMH ( +) group (n = 6), the mean logMAR BCVA significantly deterioratedfrom 0.59 ± 0.45 at baseline to 0.88 ± 0.47 at the final visit (P = 0.024). No significant BCVA changes were observed in the tAMD-SMH (-) (n = 45), PCV-SMH ( +) (n = 12), or PCV-SMH (-) (n = 64) groups (all P > 0.05). The tAMD-SMH ( +) group showed a significantly higher incidence of macular fibrosis at the final visit than did the tAMD-SMH (-) group (P = 0.042). There was no influence of baseline SMH on the macular fibrosis incidence in eyes with PCV and the macular atrophy incidence in eyes with tAMD and PCV. The presence of SMH at baseline resulted in poorer long-term visual acuity in eyes with tAMD, even with aflibercept treatment. However, no such influence was observed in eyes with PCV.

The Reinforced Treat-and-Extend Protocol for Exudative Age-Related Macular Degeneration: Retrospective Assessment of 24-Month Real-World Outcomes in France.

The aim of this work is to evaluate the real-world outcomes of the reinforced treat-and-extend (RTE) protocol for the treatment of exudative age-related macular degeneration with intravitreal injections of aflibercept or ranibizumab (anti-vascular endothelial growth factor therapies). This was a retrospective review of patients from two tertiary ophthalmology centers in France initiating the RTE protocol between February 2018 and June 2021. The primary outcome was change in best-corrected visual acuity (BCVA) after 24months. Secondary outcomes were change in central retinal thickness (CRT), recurrence, and management-related factors (injection interval, number of injections/consultations). Outcomes were additionally evaluated after protocol changes (strict versus modified RTE protocol groups). Sixty-eight patients (72 eyes) were included (68% females; mean age 82.2 ± 7.8years). After 24months, mean BCVA significantly improved (65.22 ± 14 vs. 71.96 ± 13 Early Treatment Diabetic Retinopathy Study letters; p < 0.001) and CRT significantly decreased (388.6 ± 104 vs. 278.8 ± 51μM; p < 0.001) with 21% of eyes showing signs of exudation. Over the 24months, a mean total of 14.9 ± 4.0 injections and 8.6 ± 1.4 consultations were performed. Mean 24-month injection interval was 7.9 ± 2.3weeks. Initial and 24-month ophthalmic outcomes for eyes in the strict (47%) versus modified (53%) groups were not significantly different, but mean time interval to first recurrence of disease activity was significantly shorter for the modified group (7.3 ± 2.4 vs. 9.9 ± 2.5weeks; p < 0.001). Patients in the strict RTE group received significantly less injections (13.9 ± 3.6 vs. 16.5 ± 3.9; p = 0.006) and mean 24-month injection interval was significantly longer (9.5 ± 2.7 vs. 6.5 ± 2.1weeks; p < 0.001). Consultation number was similar (8.5 ± 1.9 vs. 8.8 ± 1.6; p = 0.93). Treatment with aflibercept versus ranibizumab did not influence ophthalmic or management outcomes. The RTE protocol, even when modified, reduced consultations but improved ophthalmic outcomes. The RTE protocol could reduce hospital visits and overall burden while also encouraging better patient compliance. Video Abstract available for this article. Vincent Soler and François-Philippe Roubelat summarize the Reinforced Treat-and-Extend Protocol and main results (MP4 225022 KB).

Artemisinin Confers Cytoprotection toward Hydrogen Peroxide-Induced Cell Apoptosis in Retinal Pigment Epithelial Cells in Correlation with the Increased Acetylation of Histone H4 at Lysine 8.

Increased oxidative stress is one of the critical pathologies inducing age-related macular degeneration (AMD), characterized by retinal pigment epithelial (RPE) cell damage and death. The unbalanced acetylation and deacetylation of histones have been implicated in AMD pathogenesis or hydrogen peroxide (H2O2)-induced cell damage. Therefore, strategies aimed at controlling the balance between acetylation and deacetylation may effectively protect RPE cells from oxidative damage. Artemisinin is an antimalarial lactone drug derived from Artemisia annua, with antioxidant activity known to modulate histone acetylation in the brain, but its effect on the retina is unknown. In this study, we aimed to investigate whether Artemisinin exerts a cytoprotective effect on oxidative stress-induced apoptosis in RPE cells by regulating histone acetylation. We hypothesized that Artemisinin confers cytoprotection toward H2O2-induced apoptosis in RPE cells through this mechanism. In the present study, we found that Artemisinin at a sub-clinic dosage of 20 μM inhibited the H2O2-induced cell viability decrease and B-cell lymphoma 2 (Bcl-2) protein level decrease and attenuated the H2O2-induced decrease in the histone H4 lysine (Lys) 8 acetylation [Acetyl-H4 (Lys 8)] level in the retinal RPE cell line D407. As expected, histone deacetylase inhibitor Trichostatin A at the concentration of 250 nM increased the Acetyl-H4 (Lys 8) level in D407 cells and attenuated the H2O2-induced cell viability decrease and apoptosis. Similar findings were obtained using adult RPE (ARPE)19 cells, another human RPE cell line, and primary human RPE cell cultures. In conclusion, these results confirmed our hypothesis and indicated that Artemisinin attenuated H2O2-induced apoptosis in apparent correlation with the increase in the Acetyl-H4 (Lys 8) level, which is associated with gene transcription and cell survival. By modulating histone acetylation, Artemisinin may restore the balance between acetylation and deacetylation and enhance the resistance and survival of RPE cells under oxidative stress. Our study provides novel mechanistic insights into the effect of Artemisinin on histone acetylation and apoptosis in RPE cells and supports the potential application of Artemisinin in the prevention and/or treatment of AMD.

Inhibition of HDAC1 and 3 in the Presence of Systemic Inflammation Reduces Retinal Degeneration in a Model of Dry Age-Related Macular Degeneration.

Purpose: Previously, we identified increased retinal degeneration and cytokine response in a mouse model of dry age-related macular degeneration (AMD) in the presence of systemic inflammation from rheumatoid arthritis (RA). Histone deacetylases (HDACs) regulate cytokine production by reducing acetylation and are found to be dysregulated in inflammatory diseases, including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation. Methods: Collagen induced arthritis (CIA) was induced in C57BL6J mice, followed by sodium iodate (NaIO3)-induced retinal degeneration. Mice were treated with a selective HDAC class I inhibitor, MS-275, and retinal structure [optical coherence tomography (OCT)], function (electroretinography), and molecular changes quantitative real-time polymerase chain reaction (RT-qPCR, Western Blot) were assessed. Results: NaIO3 retinal damage was diminished in CIA mice treated with MS-275 (P ≤ 0.05). While no significant difference was observed in retinal pigment epithelium (RPE) function, a trend in increased c-wave amplitude was detected in CIA + NaIO3 mice treated with MS-275. Finally, we identified decreased Hdac1, Hdac3, and Cxcl9 expression in CIA + NaIO3 mouse RPE/choroid when treated with MS-275 (P ≤ 0.05). Conclusions: Our data demonstrate that HDAC inhibition can reduce the additive effect of NaIO3-induced retinal degeneration in the presence of systemic inflammation by CIA as measured by OCT analysis. In addition, HDAC inhibition in CIA + NaIO3 treated mice resulted in reduced cytokine production. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for dry AMD treatment.

The antioxidant effect of tetrahedral framework nucleic acid-based delivery of small activating RNA targeting DJ-1 on retinal oxidative stress injury.

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the world's leading causes of blindness. The retinal pigment epithelium (RPE) and vascular endothelial cell exposed to oxidative stress is the major cause of AMD and DR. DJ-1, an important endogenous antioxidant, its overexpression is considered as a promising antioxidant treatment for AMD and DR. Here, we modified the tetrahedral frame nucleic acids (tFNAs) with DJ-1 saRNAs as a delivery system, and synthesized a novel nanocomplex (tFNAs-DJ-1 saRNAs). In vitro studies show that tFNAs-DJ-1 saRNAs can efficiently transfer DJ-1 saRNAs to human umbilical vein endothelial cells (HUVECs) and ARPE-19s, and significantly increased their cellular DJ-1 level. Reactive oxygen species expression in H2O2-treated HUVECs and ARPE-19s were decreased, cell viability was enhanced and cell apoptosis were inhibited when tFNAs-DJ-1 saRNAs were delivered. Moreover, tFNAs-DJ-1 saRNAs preserved mitochondrial structure and function under oxidative stress conditions. In the aspect of molecular mechanism, tFNAs-DJ-1 saRNAs activated Erk and Nrf2 pathway, which might contribute to its protective effects against oxidative stress damage. To conclude, this study shows the successfully establishment of a simple but effective delivery system of DJ-1 saRNAs associated with antioxidant effects in AMD and DR, which may be a promising agent for future treatment in oxidative stress-related retinal disorders.

Understanding the Impact of Polyunsaturated Fatty Acids on Age-Related Macular Degeneration: A Review.

Age-related Macular Degeneration (AMD) is a multifactorial ocular pathology that destroys the photoreceptors of the macula. Two forms are distinguished, dry and wet AMD, with different pathophysiological mechanisms. Although treatments were shown to be effective in wet AMD, they remain a heavy burden for patients and caregivers, resulting in a lack of patient compliance. For dry AMD, no real effective treatment is available in Europe. It is, therefore, essential to look for new approaches. Recently, the use of long-chain and very long-chain polyunsaturated fatty acids was identified as an interesting new therapeutic alternative. Indeed, the levels of these fatty acids, core components of photoreceptors, are significantly decreased in AMD patients. To better understand this pathology and to evaluate the efficacy of various molecules, in vitro and in vivo models reproducing the mechanisms of both types of AMD were developed. This article reviews the anatomy and the physiological aging of the retina and summarizes the clinical aspects, pathophysiological mechanisms of AMD and potential treatment strategies. In vitro and in vivo models of AMD are also presented. Finally, this manuscript focuses on the application of omega-3 fatty acids for the prevention and treatment of both types of AMD.