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Prevention and Treatments of Age-Related Macular Degeneration

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Ophthalmology".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 17343

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Prof. Dr. Margaret M. DeAngelis

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Guest Editor

Ross Eye Institute, Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14215, USA
Interests: age-related macular degeneration; complex blinding diseases; epigenetics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Lindsay A. Farrer

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Guest Editor

Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA
Interests: clinical trials; epigenetics; genomics; angiogenesis; personalized and precision medicine; metabolomics; proteomics; gene expression; extracellular RNA; disease mechanism; induced pluripotent stem cells; primary cell lines; organoids; imaging; phenotyping; in vivo and in vitro models of AMD; AMD and diseases with overlapping pathophysiology; big data
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Age-related macular degeneration remains the leading cause of visual impairment in those over 60 years of age. To date, anit-vegf therapies for late-stage disease, the neovascular subtype, have been used to treat the disease, but they are not a cure. There is currently no treatment for the other end-stage of AMD, the geographic atrophic (GA) subtype, or the intermediate or earlier forms of AMD. Current understanding of local disease pathophysiology in AMD is limited. Moreover, whether or not some aspects of AMD are localized, systemic or a combination of both is also unclear. There is no animal model which faithfully recapitulates the clinical spectrum of AMD. Therefore, understanding AMD disease mechanisms or the functional consequence of associated genetic variation can be challenging. In vitro assays can complement in vivo models, and many groups are currently working to develop such assays. Studies that incorporate standardized phenotyping of source material (DNA, RNA, and/or protein) coupled with in vitro and/or in vivo assays would help in the development of novel translational treatment and prevention options, particularly for earlier forms of AMD.

Prof. Dr. Margaret M. DeAngelis
Prof. Dr. Lindsay A. Farrer
Guest Editors

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Keywords

clinical trials
epigenetics
genomics
angiogenesis
personalized and precision medicine
metabolomics
proteomics
gene expression
extracellular RNA
disease mechanism
induced pluripotent stem cells
primary cell lines
organoids
imaging
phenotyping
in vivo and in vitro models of AMD
AMD and diseases with overlapping pathophysiology
big data

Published Papers (5 papers)

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Research

16 pages, 5381 KiB

Open AccessArticle

Bone Morphogenetic Protein (BMP)4 But Not BMP2 Disrupts the Barrier Integrity of Retinal Pigment Epithelia and Induces Their Migration: A Potential Role in Neovascular Age-Related Macular Degeneration

by Ahmed S. Ibrahim, Khaled Hussein, Fang Wang, Ming Wan, Nancy Saad, Maamon Essa, Ivana Kim, Akbar Shakoor, Leah A. Owen, Margaret M. DeAngelis and Mohamed Al-Shabrawey

J. Clin. Med. 2020, 9(7), 2293; https://doi.org/10.3390/jcm9072293 - 19 Jul 2020

Cited by 11 | Viewed by 3602

Abstract

Disruption of retinal pigment epithelial (RPE) barrier integrity and RPE migration are hallmark features in neovascular age-related macular degeneration (nAMD), but the underlying causes and pathophysiology are not completely well-defined. Herein, we aimed to evaluate the effect of bone morphogenetic proteins (BMPs) on the barrier function and migration of RPE. In particular, we investigated the role of BMP2 and BMP4 in these processes as our analysis of RNA-sequencing (seq) data from human donor eyes demonstrated that they are highly differentially expressed BMP members in macular RPE/choroid versus macular retina. We used electrical cell-substrate impedance sensing (ECIS) system to monitor precisely in real time the barrier integrity and migration of ARPE-19 after treatment with various concentrations of BMP2 or BMP4. Immunofluorescence was also used to assess the changes in the expression and the organization of the key tight junction protein, zona occludens (ZO)-1, in ARPE-19 cells under BMP2 or BMP4 treatment. This was followed by measuring the activity of matrix metalloproteinases (MMPs). Finally, RNA-seq and ELISA were used to determine the local and circulating levels of BMP2 and BMP4 in retinas and serum samples from nAMD donors. Our ECIS results showed that BMP4 but not BMP2 decreased the transcellular electrical resistance (TER) of ARPE-19 and increased their migration in comparison with control (vehicle-treated cells). Furthermore, immunofluorescence showed a disorganization of ZO-1 in BMP4-treated ARPE-19 not in BMP2-treated cells or vehicle-treated controls. This effect of BMP4 was associated with significant increases in the activity of MMPs, specifically MMP2. Lastly, these results were corroborated by additional findings that circulating but not local BMP4 levels were significantly higher in nAMD donor samples compared to controls. Collectively, our results demonstrated unreported effects of BMP4 on inducing RPE dysfunction and suggest that BMP4 but not BMP2 may represent a potential therapeutic target in nAMD. Full article

(This article belongs to the Special Issue Prevention and Treatments of Age-Related Macular Degeneration)

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10 pages, 1467 KiB

Open AccessArticle

Macular Pigment Optical Density and Photoreceptor Outer Segment Length as Predisease Biomarkers for Age-Related Macular Degeneration

by Norihiro Nagai, Sakiko Minami, Misa Suzuki, Hajime Shinoda, Toshihide Kurihara, Hideki Sonobe, Kazuhiro Watanabe, Atsuro Uchida, Norimitsu Ban, Kazuo Tsubota and Yoko Ozawa

J. Clin. Med. 2020, 9(5), 1347; https://doi.org/10.3390/jcm9051347 - 05 May 2020

Cited by 12 | Viewed by 2652

Abstract

To explore predisease biomarkers, which may help screen for the risk of age-related macular degeneration (AMD) at very early stages, macular pigment optical density (MPOD) and photoreceptor outer segment (PROS) length were analyzed. Thirty late AMD fellow eyes, which are at high risk and represent the predisease condition of AMD, were evaluated and compared with 30 age-matched control eyes without retinal diseases; there was no early AMD involvement in the AMD fellow eyes. MPOD was measured using MPS2^® (M.E. Technica Co. Ltd., Tokyo, Japan), and PROS length was measured based on optical coherence tomography images. MPOD levels and PROS length in the AMD fellow eyes were significantly lower and shorter, respectively, than in control eyes. MPOD and PROS length were positively correlated in control eyes (R = 0.386; p = 0.035) but not in AMD fellow eyes. Twenty (67%) AMD fellow eyes met the criteria of MPOD < 0.65 and/or PROS length < 35 μm, while only five (17%) control eyes did. After adjusting for age and sex, AMD fellow eyes more frequently satisfied the definition (p < 0.001; 95% confidence interval, 3.50–60.4; odds ratio, 14.6). The combination of MPOD and PROS length may be a useful biomarker for screening predisease AMD patients, although further studies are required in this regard. Full article

(This article belongs to the Special Issue Prevention and Treatments of Age-Related Macular Degeneration)

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15 pages, 2215 KiB

Open AccessArticle

Long-Term Treatment Outcomes in Type 3 Neovascularization: Focus on the Difference in Outcomes between Geographic Atrophy and Fibrotic Scarring

by Jae Hui Kim, Jong Woo Kim, Chul Gu Kim and Dong Won Lee

J. Clin. Med. 2020, 9(4), 1145; https://doi.org/10.3390/jcm9041145 - 16 Apr 2020

Cited by 11 | Viewed by 2538

Abstract

Background: To evaluate the difference in the long-term treatment outcomes of type 3 neovascularization between eyes with geographic atrophy and those with fibrotic scars. Methods: This retrospective study included 195 eyes diagnosed with type 3 neovascularization and treated with anti-vascular endothelial growth factor (VEGF) agents. The included eyes were divided into three groups according to the fundus findings at the final visit: patients with fovea-involving geographic atrophy (GA group), patients with fovea-involving fibrotic scars (scar group), and patients with no fovea-involving geographic atrophy or fibrotic scars (non-GA/scar group). The best-corrected visual acuities (BCVA) of the three groups at the final visits were compared. Results: The mean follow-up period was 47.5 ± 20.7 months. The mean logMAR BCVA at the final visit was 1.18 ± 0.58 in the GA group (n = 58), 1.67 ± 0.58 in the scar group (n = 62), and 0.69 ± 0.64 in the non-GA/scar group (n = 75). The BCVA was significantly worse in the scar group than in the GA (p < 0.001) and the non-GA/scar groups (p < 0.001). Conclusion: Eyes with fibrotic scars showed the poorest visual outcomes in type 3 neovascularization among the studied groups. Preventing the development of fibrotic scars should be considered an important treatment goal. Full article

(This article belongs to the Special Issue Prevention and Treatments of Age-Related Macular Degeneration)

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13 pages, 959 KiB

Open AccessArticle

A Pilot Study Evaluating the Effects of 670 nm Photobiomodulation in Healthy Ageing and Age-Related Macular Degeneration

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

J. Clin. Med. 2020, 9(4), 1001; https://doi.org/10.3390/jcm9041001 - 02 Apr 2020

Cited by 15 | Viewed by 4493

Abstract

Limited evidence suggests that the application of 670 nm of red light alters the course of aged decline. A previous report on 18 patients showed regression of drusen and improvement in visual functions in patients with intermediate age-related macular degeneration (AMD) by 12 months. We evaluated the functional and structural effects of applying 670 nm light to 31 patients with intermediate AMD and 11 people aged 55 years or above with normal retina. The study eyes were treated daily in the morning with a 670 nm hand-held light source housed in a torch-like tube that emitted energy equivalent to 40 mW/cm² or 4.8J/ cm² for 2 min at the viewing aperture. Visual function in terms of best-corrected visual acuity, low luminance visual acuity, scotopic thresholds and rod-intercept time were compared between baseline and 1, 3, 6 and 12 months. Structural changes on optical coherence tomography OCT and colour photographs were also assessed. Five withdrew consent voluntarily due to the intensity of the study visit assessments and two developed neovascular AMD and were excluded from further treatment and the analysis. In normal ageing, there was an improvement in scotopic thresholds in the group with no AMD by 1.77dB (p = 0.03) and no other parameters showed any clinically significant change. In eyes with intermediate AMD, there was no significant improvement in any functional or structural changes at any time point up to 12 months although the compliance was good. This pilot study shows that photobiomodulation with 670 nm has no effect in patients who have already progressed to intermediate AMD. Full article

(This article belongs to the Special Issue Prevention and Treatments of Age-Related Macular Degeneration)

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10 pages, 1080 KiB

Open AccessArticle

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

by Juan M. Chao de la Barca, Barnabé Rondet-Courbis, Marc Ferré, Jeanne Muller, Adrien Buisset, Stéphanie Leruez, Guillaume Plubeau, Thibaut Macé, Laurie Moureauzeau, Stéphanie Chupin, Lydie Tessier, Odile Blanchet, Guy Lenaers, Vincent Procaccio, Delphine Mirebeau-Prunier, Gilles Simard, Philippe Gohier, Dan Miléa and Pascal Reynier

J. Clin. Med. 2020, 9(3), 631; https://doi.org/10.3390/jcm9030631 - 27 Feb 2020

Cited by 21 | Viewed by 3148

Abstract

To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini–Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria; proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency. Full article

(This article belongs to the Special Issue Prevention and Treatments of Age-Related Macular Degeneration)

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