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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 18558

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Dr. Oyuna Kozhevnikova

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Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: retina; AMD; aging; autophagy; transcriptome; animal model; RPE; oxidative stress; neurodegeneration; Alzheimer’s disease; chloroquine; medical genetics; retinopathy; anti-VEGF; neovascular AMD

Special Issue Information

Dear Colleagues,

Age-related macular degeneration (AMD) is an eye disease that is the main cause of irreversible vision loss in people over 60 years of age. Due to the aging of the global population predicted in the coming decades, the number of patients with AMD is expected to increase significantly. AMD is a disease of a complex nature, the development of which is controlled by many interacting genetic and environmental factors that determine the form, rate of disease progression, and response to therapy.

The pathogenesis of AMD is based on a decrease in metabolic and regenerative processes characteristic of aging, a violation of the microcirculation and structural organization of the retina, the prerequisites and mechanisms for the transition of which into the pathological process remain unclear. Therefore, studies of the molecular mechanisms of AMD pathogenesis and new approaches to its early diagnostics, treatments, and prevention are urgently needed. In this Special Issue of the journal Biomedicines, we would like to invite you to provide original clinical and experimental studies and reviews on all aspects related to the theme of “Advanced Research in AMD”. Submissions dealing with the topics mentioned in the keywords listed below are welcome.

Dr. Oyuna Kozhevnikova
Guest Editor

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Keywords

dry AMD pathogenesis
neovascular age-related macular degeneration
optical coherence tomography and angiography
anti-VEGF resistance and incomplete response to anti-VEGF therapy
early diagnosis biomarkers
biomarkers for predicting treatment response
lipofusciogenesis and drusogenesis in AMD
oxidative stress and antioxidant system in AMD
chronic inflammation and complement system dysregulation in AMD
AMD genetics: mutations and polymorphisms of genes related to AMD
epigenetics and miRNA regulation in AMD
AMD animal and cell models

Published Papers (11 papers)

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Editorial

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4 pages, 182 KiB

Open AccessEditorial

Advanced Research in Age-Related Macular Degeneration: Special Issue

by Oyuna Kozhevnikova

Biomedicines 2024, 12(2), 392; https://doi.org/10.3390/biomedicines12020392 - 08 Feb 2024

Viewed by 685

Abstract

Age-related macular degeneration (AMD) is an eye disease that is the leading cause of irreversible vision loss in people over 55 years of age [...] Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

Research

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25 pages, 1270 KiB

Open AccessArticle

Association of STAT4 Gene Polymorphisms (rs10181656, rs7574865, rs7601754, rs10168266) and Serum STAT4 Levels in Age-Related Macular Degeneration

by Tomas Blekeris, Greta Gedvilaite, Kriste Kaikaryte, Loresa Kriauciuniene, Dalia Zaliuniene and Rasa Liutkevciene

Biomedicines 2024, 12(1), 18; https://doi.org/10.3390/biomedicines12010018 - 20 Dec 2023

Cited by 2 | Viewed by 675

Abstract

Age-related macular degeneration (AMD) is a progressive degenerative disease that affects the central part of the retina: the macula. AMD is the most common cause of central vision loss in industrialized countries. Increasing attention is being paid to the study of genetic factors that may influence the manifestation of AMD. STAT4 protein is involved in the pathogenesis of numerous inflammatory processes, so we decided to investigate the association between STAT4 gene polymorphisms (rs10181656, rs7574865, rs7601754, and rs10168266) and age-related macular degeneration. Purpose: To investigate the association between STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) gene polymorphisms and STAT4 serum levels in patients with age-related macular degeneration. Methods and participants: The study included 150 individuals with early AMD, 150 individuals with exudative AMD, and 200 healthy subjects. DNA was extracted from peripheral blood leukocytes using the DNA salting-out method, and the genotyping was performed using a real-time polymerase chain reaction (RT-PCR) method. STAT4 serum levels were evaluated using the ELISA method. Statistical analysis was performed using “IBM SPSS “Statistics 29.0” software”. Results: The study revealed no statistically significant differences in the distribution of genotypes and alleles for the STAT4 polymorphisms (rs10181656, rs7574865, rs7601754, and rs10168266) between patients with AMD and the control group. Similarly, a gender-based analysis did not yield any significant differences in the genotype or allele frequencies. Age group comparisons also showed no statistically significant variations in the presence of these STAT4 polymorphisms between AMD patients and the control group. However, notably, individuals with exudative AMD displayed lower levels of serum STAT4 in comparison to the control group (median (IQR): 0.118 (0.042) vs. 0.262 (0.385), p = 0.005). Conclusion: Investigating STAT4 gene polymorphisms (rs10181656, rs7574865, rs7601754, and rs10168266) did not reveal a significant association with AMD. However, further analysis demonstrated intriguing findings regarding serum STAT4 levels. Exudative AMD patients with at least one G allele of the STAT4 rs10181656 exhibited significantly lower serum STAT4 levels than the control group subjects (p = 0.011). Similarly, those with at least one T allele of STAT4 rs10168266 had lower serum STAT4 levels compared to the control group subjects (p = 0.039). These results suggest a potential link between specific STAT4 genotypes and serum STAT4 levels in exudative AMD patients, shedding light on a novel aspect of the disease. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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13 pages, 615 KiB

Open AccessArticle

Pharmacogenetic Association between Allelic Variants of the Autophagy-Related Genes and Anti-Vascular Endothelial Growth Factor Treatment Response in Neovascular Age-Related Macular Degeneration

by Oyuna S. Kozhevnikova, Anzhella Zh. Fursova, Anna S. Derbeneva, Ida F. Nikulich, Vasiliy A. Devyatkin and Nataliya G. Kolosova

Biomedicines 2023, 11(11), 3079; https://doi.org/10.3390/biomedicines11113079 - 16 Nov 2023

Cited by 1 | Viewed by 997

Abstract

Background: Age-related macular degeneration (AMD) is the leading cause of late-onset blindness in elderly. The occurrence and development of AMD is a multifactorial complex process where autophagy plays an important role. The first-line drugs for neovascular AMD (nAMD) are inhibitors of VEGF, with up to 30% of patients having an incomplete response to treatment. Genetic factors may influence the response to anti-VEGF therapy and explain treatment outcome variability. We aimed to estimate the role of polymorphic markers of the MTOR (rs1064261, rs1057079, rs11121704, rs2295080), SQSTM1 (rs10277), ULK1 (rs11246867, rs3088051), MAP1LC3A (rs73105013) and ATG5 (rs573775) genes in the development of nAMD and the efficacy of anti-VEGF therapy response. Methods: Genotyping by allele-specific PCR was performed in 317 controls and 315 nAMD patients in the Russian population. Of them, 196 treatment-naive nAMD patients underwent three monthly intravitreal injections (IVIs) of aflibercept. Genotypic frequencies were compared with OCT markers of therapy effectiveness and best-corrected visual acuity (BCVA) measures. The main outcomes were the BCVA gain and decrease in central retinal thickness (CRT). Results: MTOR-rs1057079-C, MTOR-rs11121704-C and MTOR-rs2295080-G alleles were associated with an increased risk of nAMD. The BCVA was increased in 117 (59.7%) patients by 10 [5–20] letters, did not changed in 59 (30.1%), and was decreased in 20 (10.2%) patients. ULK1-rs3088051 was associated with BCVA change. Among patients with the TT and CT genotypes for ULK1-rs3088051, an improvement in visual acuity was noted in 67.6% and 53.8% of cases, while in patients with the CC genotype, an increase in BCVA was recorded in 37.5% of cases (p = 0.01). The decrease in CRT was associated with SQSTM1-rs10277 (p = 0.001): it was significantly higher in TT (93 [58–122] mkm) and CT (66 [30–105] mkm) carriers compared to the CC genotype (47 [24–68] mkm). Other SNPs did not show significant associations with the outcome of anti-VEGF treatment. Conclusions: MTOR gene polymorphisms are moderately associated with the risk of nAMD. SQSTM1-rs10277 and ULK1-rs3088051 may influence short-term response to intravitreal anti-VEGF treatment. The results suggest that autophagy could be a target for future drugs to overcome resistance to anti-VEGF therapy. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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18 pages, 4624 KiB

Open AccessArticle

Advanced ImageJ Analysis in Degenerative Acquired Vitelliform Lesions Using Techniques Based on Optical Coherence Tomography

by Ioana Damian, George-Adrian Muntean, Larisa-Bianca Galea-Holhoș and Simona-Delia Nicoară

Biomedicines 2023, 11(5), 1382; https://doi.org/10.3390/biomedicines11051382 - 06 May 2023

Cited by 1 | Viewed by 1689

Abstract

Acquired vitelliform lesions (AVLs) are associated with a large spectrum of retinal diseases, among which is age-related macular degeneration (AMD). The purpose of this study was to characterize AVLs’ evolution in AMD patients using optical coherence tomography (OCT) technology and ImageJ software. We measured AVLs’ size and density and followed their impacts over surrounding retinal layers. Average retinal pigment epithelium (RPE) thickness in the central 1 mm quadrant (45.89 ± 27.84 µm vs. 15.57 ± 1.40 µm) was significantly increased, as opposed to the outer nuclear layer (ONL) thickness, which was decreased (77.94 ± 18.30 µm vs. 88.64 ± 7.65 µm) in the vitelliform group compared to the control group. We found a continuous external limiting membrane (ELM) in 55.5% of the eyes compared to a continuous ellipsoid zone (EZ) in 22.2% of the eyes in the vitelliform group. The difference between the mean AVLs’ volume at baseline compared to the last visit for the nine eyes with ophthalmologic follow-up was not statistically significant (p = 0.725). The median follow-up duration was 11 months (range 5–56 months). Seven eyes (43.75%) were treated with intravitreal anti-vascular endothelium growth factor (anti-VEGF) agent injections, in which we noted a 6.43 ± 9 letter decrease in the best-corrected visual acuity (BCVA). The increased RPE thickness could suggest hyperplasia contrary to the decreased ONL, which could mirror the impact of the vitelliform lesion on photoreceptors (PR). Eyes that received anti-VEGF injections did not show signs of improvement regarding BCVA. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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11 pages, 3348 KiB

Open AccessArticle

Quantitative Autofluorescence in Non-Neovascular Age Related Macular Degeneration

by Shruti Chandra, Manjot K. Grewal, Sarega Gurudas, Rajan Sondh, Alan Bird, Glen Jeffery, Victor Chong and Sobha Sivaprasad

Biomedicines 2023, 11(2), 560; https://doi.org/10.3390/biomedicines11020560 - 15 Feb 2023

Cited by 2 | Viewed by 1396

Abstract

Quantitative autofluorescence (qAF8) level is a presumed surrogate marker of lipofuscin content in the retina. We investigated the changes in the qAF8 levels in non-neovascular AMD. In this prospective cohort study, Caucasians aged ≥50 years with varying severity of non-neovascular AMD in at least one eye and Snellen visual acuity ≥6/18 were recruited. The qAF8 levels were analysed in the middle eight segments of the Delori pattern (HEYEX software, Heidelberg, Germany). The AMD categories were graded using both the Beckman classification and multimodal imaging (MMI) to include the presence of subretinal drusenoid deposits (SDD). A total of 353 eyes from 231 participants were analyzed. Compared with the age-matched controls, the qAF8 values decreased in the eyes with AMD (adjusted % difference = −19.7% [95% CI −28.8%, −10.4%]; p < 0.001) and across the AMD categories, (adjusted % differences; Early, −13.1% (−24.4%, −1%), p = 0.04; intermediate AMD (iAMD), −22.9% (−32.3%, −13.1%), p < 0.001; geographic atrophy −25.2% (−38.1%, −10.4%), p = 0.002). On MMI, the qAF8 was reduced in the AMD subgroups relative to the controls, (adjusted % differences; Early, −5.8% (−18.9%, 8.3%); p = 0.40; iAMD, −26.7% (−36.2%, −15.6%); p < 0.001; SDD, −23.7% (−33.6%, −12.2%); p < 0.001; atrophy, −26.7% (−39.3%, −11.3%), p = 0.001). The qAF8 levels declined early in AMD and were not significantly different between the severity levels of non-neovascular AMD, suggesting the early and sustained loss of function of the retinal pigment epithelium in AMD. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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16 pages, 5507 KiB

Open AccessArticle

Suppression of Age-Related Macular Degeneration-like Pathology by c-Jun N-Terminal Kinase Inhibitor IQ-1S

by Anna A. Zhdankina, Dmitry I. Tikhonov, Sergey V. Logvinov, Mark B. Plotnikov, Andrei I. Khlebnikov and Nataliya G. Kolosova

Biomedicines 2023, 11(2), 395; https://doi.org/10.3390/biomedicines11020395 - 29 Jan 2023

Cited by 4 | Viewed by 1657

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. The development of AMD is associated with inflammation, oxidative stress, and progressive proteostasis imbalance, in the regulation of which c-Jun N-terminal kinases (JNK) play a crucial role. JNK inhibition is discussed as an alternative way for prevention and treatment of AMD and other neurodegenerative diseases. Here we assess the retinoprotective potential of the recently synthesized JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S) using senescence-accelerated OXYS rats as a model of AMD. The treatment with IQ-1S (50 mg/kg body weight intragastric) during the period of active disease development (from 4.5 to 6 months of age) improved some (but not all) histological abnormalities associated with retinopathy. IQ-1S improved blood circulation, increased the functional activity of the retinal pigment epithelium, reduced the VEGF expression in the endothelial cells, and increased the expression of PEDF in the neuroretina. The result was a decrease in the degeneration of photoreceptors and neurons of the inner layers. IQ-1S significantly improved the retinal ultrastructure and increased the number of mitochondria, which were significantly reduced in the neuroretina of OXYS rats compared to Wistar rats. It seems probable that using IQ-1S can be a good prophylactic strategy to treat AMD. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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10 pages, 633 KiB

Open AccessArticle

Association between Age-Related Macular Degeneration and the Risk of Diabetes Mellitus: A Nationwide Cohort Study

by Wonyoung Jung, Je Moon Yoon, Kyungdo Han, Bongseong Kim, Sungsoon Hwang, Dong Hui Lim and Dong Wook Shin

Biomedicines 2022, 10(10), 2435; https://doi.org/10.3390/biomedicines10102435 - 29 Sep 2022

Cited by 3 | Viewed by 1633

Abstract

Age-related macular degeneration (AMD) is a degenerative and progressive disease of the macula, the part of the retina that is responsible for central vision. AMD shares some risk factors with diabetes mellitus (DM), but little is known about the risk of DM in individuals with AMD. With the goal of establishing novel perspectives, this study aimed to investigate the association between AMD and the risk of DM using the Korean Nationwide Health Insurance Database. Individuals aged ≥ 50 years who underwent a national health screening program in 2009 were enrolled. Participants were categorized by the presence of AMD and visual disability (VD). The Cox hazard regression model was used to examine hazard ratios (HRs) of DM with adjustment for potential confounders. Stratified analyses by age, sex, and comorbidities (hypertension or dyslipidemia) were also performed. During a mean follow-up of 8.61 years, there were 403,367 (11.76%) DM incidences among the final 3,430,532 participants. The crude HR (95% confidence interval (CI)) was 1.16 (1.13–1.20) for AMD. After adjusting for potential confounders, AMD was associated with a 3% decreased risk of DM (aHR 0.97, 95% CI 0.95–1.00), but no significant association with the risk of DM was found in AMD with VD (aHR 1.03, 95% CI 0.93–1.14). In summary, we did not find an increased risk of DM in individuals with AMD. A 3% decreased risk of DM in patients with AMD is not clinically meaningful. Our study suggests that the association between AMD and the risk of DM is weak, considering the potential confounders. Further studies examining this association are needed to extend our knowledge. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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9 pages, 1099 KiB

Open AccessArticle

Correlation between Macular Neovascularization (MNV) Type and Druse Type in Neovascular Age-Related Macular Degeneration (AMD) Based on the CONAN Classification

by Daniel Rudolf Muth, Mario Damiano Toro, Anahita Bajka, Kamil Jonak, Roman Rieder, Myrtha Magdalena Kohler, Jeanne Martine Gunzinger, Eric H. Souied, Michael Engelbert, K. Bailey Freund and Sandrine Anne Zweifel

Biomedicines 2022, 10(10), 2370; https://doi.org/10.3390/biomedicines10102370 - 22 Sep 2022

Cited by 2 | Viewed by 1602

Abstract

To investigate associations and predictive factors between macular neovascularization (MNV) lesion variants and drusen types in patients with treatment-naïve neovascular age-related macular degeneration (AMD). Methods: Multimodal imaging was retrospectively reviewed for druse type (soft drusen, subretinal drusenoid deposits (SDDs) or mixed) and MNV type (MNV 1, MNV 2, MNV 1/2 or MNV 3). The Consensus on Neovascular AMD Nomenclature (CONAN) classification was used for characterizing MNV at baseline. Results: One eye of each eligible patient was included (n = 191). Patients with predominant SDDs had an increased adjusted odds ratio (aOR) for MNV 2 (23.4453, p = 0.0025) and any type of MNV 3 (8.7374, p < 0.0001). Patients with MNV 1/2 had an aOR for predominant SDDs (0.3284, p = 0.0084). Patients with MNV1 showed an aOR for SDDs (0.0357, p < 0.0001). Eyes with SDDs only without other drusen types showed an aOR for MNV 2 (9.2945, p < 0.0001). Conclusions: SDDs represent a common phenotypic characteristic in AMD eyes with treatment-naïve MNV. The aOR for eyes with predominant SDDs to develop MNV 2 and MNV 3 was much higher, possibly due to their location in the subretinal space. The predominant druse type may help to predict which type of MNV will develop during the course of AMD. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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Review

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17 pages, 572 KiB

Open AccessReview

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

by Prem N. Patel, Parth A. Patel, Matthew R. Land, Ibrahim Bakerkhatib-Taha, Harris Ahmed and Veeral Sheth

Biomedicines 2022, 10(8), 1884; https://doi.org/10.3390/biomedicines10081884 - 04 Aug 2022

Cited by 9 | Viewed by 3484

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly population. AMD is characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). Regarding the latter type, there is growing evidence supporting an association between the pathophysiology of dry AMD and key proteins in the complement cascade. The complement cascade works as a central part of the innate immune system by defending against foreign pathogens and modified self-tissues. Through three distinct pathways, a series of plasma and membrane-associated serum proteins are activated upon identification of a foreign entity. Several of these proteins have been implicated in the development and progression of dry AMD. Potential therapeutic targets include C1q, C3, C5, complement factors (B, D, H, I), membrane attack complex, and properdin. In this review, we provide an understanding of the role of the complement system in dry AMD and discuss the emerging therapies in early phase clinical trials. The tentative hope is that these drugs may offer the potential to intervene at earlier stages in dry AMD pathogenesis, thereby preventing progression to late disease. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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Other

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13 pages, 2329 KiB

Open AccessTutorial

Methodological Appraisal of Phase 3 Clinical Trials in Geographic Atrophy

by Marc Biarnés, Xavier Garrell-Salat, Alba Gómez-Benlloch, Mercè Guarro, Gabriel Londoño, Elena López, Sergi Ruiz, Meritxell Vázquez and Laura Sararols

Biomedicines 2023, 11(6), 1548; https://doi.org/10.3390/biomedicines11061548 - 26 May 2023

Cited by 5 | Viewed by 1973

Abstract

Geographic atrophy (GA) secondary to age-related macular degeneration is a common cause of blindness worldwide. Given the recent approval of the first therapy for GA, pegcetacoplan, we critically appraise methodological aspects of the phase 3 clinical trials published so far in this disease in relation to their design, analysis and interpretation. We reviewed some of the key attributes of all phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023. The topics discussed included types of endpoints, eligibility criteria, p-value and effect size, study power and sample size, the intention to treat principle, missing data, consistency of results, efficacy–safety balance and application of results. Five phase 3 clinical trials have reported results, either partially or completely: GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE and GATE. Although there are many similarities between these trials in terms of endpoints or broad eligibility criteria, they differ in several aspects (metric of the primary endpoint, sample size, type of adverse events, etc.) that can influence the results, which are discussed. Readers should understand key methodological aspects of clinical trials to improve their interpretation. On the other hand, authors should adhere to clinical trial reporting guidelines to communicate what was done and how it was done. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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20 pages, 7325 KiB

Open AccessCase Report

Bacillary Layer Detachment in Neovascular Age-Related Macular Degeneration: Case Series

by Filomena Palmieri, Saad Younis, Walid Raslan and Lorenzo Fabozzi

Biomedicines 2023, 11(3), 988; https://doi.org/10.3390/biomedicines11030988 - 22 Mar 2023

Cited by 1 | Viewed by 1387

Abstract

Purpose: This study seeks to report the clinical and multimodal imaging findings of eight eyes of seven patients with neovascular age-related macular degeneration (nAMD) who developed bacillary layer detachment (BALAD). Setting/Venue: The patients were analysed at the Western Eye Hospital in London, UK. Methods: The approaches of this research include clinical examinations and multimodal imaging-based description of cases of nAMD with BALAD. Results: We report multimodal imaging findings of bacillary layer detachment (BALAD) in patients with nAMD. Conclusions: A bacillary layer detachment was detected in patients with neovascular age-related macular degeneration. This multimodal imaging finding is not commonly described in the literature for this disease. Full article

(This article belongs to the Special Issue Advanced Research in Age-Related Macular Degeneration (AMD))

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