scholarly journals New Technologies to Study Functional Genomics of Age-Related Macular Degeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Tu Nguyen ◽  
Daniel Urrutia-Cabrera ◽  
Roxanne Hsiang-Chi Liou ◽  
Chi D. Luu ◽  
Robyn Guymer ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
New Technologies ◽  
Cell Types ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Functional Study ◽  
Age Related

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in people over 50 years old in developed countries. Currently, we still lack a comprehensive understanding of the genetic factors contributing to AMD, which is critical to identify effective therapeutic targets to improve treatment outcomes for AMD patients. Here we discuss the latest technologies that can facilitate the identification and functional study of putative genes in AMD pathology. We review improved genomic methods to identify novel AMD genes, advances in single cell transcriptomics to profile gene expression in specific retinal cell types, and summarize recent development of in vitro models for studying AMD using induced pluripotent stem cells, organoids and biomaterials, as well as new molecular technologies using CRISPR/Cas that could facilitate functional studies of AMD-associated genes.

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

2021 ◽  
Vol 118 (41) ◽  
pp. e2102975118
Author(s):  
Meenakshi Ambati ◽  
Ivana Apicella ◽  
Shao-bin Wang ◽  
Siddharth Narendran ◽  
Hannah Leung ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Antidepressant Drugs ◽  
Drug Repurposing ◽  
Cell Types ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Dry Amd

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y 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 inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant 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 identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

scholarly journals Introduction to the multi-author review on macular degeneration

2020 ◽  
Vol 77 (5) ◽  
pp. 779-780 ◽  
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.

scholarly journals Autophagy: A new insight into pathogenesis and treatment possibilities in age-related macular degeneration

2020 ◽  
Vol 74 ◽  
pp. 213-223
Author(s):  
Agnieszka Kubicka-Trząska ◽  
Izabella Karska-Basta ◽  
Katarzyna Żuber-Łaskawiec
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Therapeutic Modalities ◽  
Central Vision Loss ◽  
Age Related ◽  
Genetic And Environmental Factors ◽  
The Impact ◽  
Insight Into

Age-related macular degeneration (AMD) is a significant problem in healthcare, because it is a leading cause of central vision loss in individuals over 50 years old in well-developed countries. Pathogenesis of AMD is multifactorial and still not completely understood. Proven risk factors include the following: natural senescence of retina, oxidative stress, complement activation, chronic subretinal inflammatory reaction, genetic and environmental factors. Data on links between autophagy and AMD development are being raised. Autophagy is a cellular process involving the degradation of long-lived proteins and damaged fragments and components of cells; it is responsible for the maintenance of dynamic intracellular homeostasis and it enables cell survival under stress conditions. Disturbances of autophagy mechanisms, i.e. its activation or inhibition, may lead to the development of many various pathologies. Thus, autophagy plays a dual role, as a mechanism responsible for protecting or killing cells. The paper describes autophagy mechanisms and their role in the natural process of retinal cells senescence and presents the autophagy impairment as a crucial cause of AMD development. We also describe the impact of intravitreal anti-VEGF therapy on retinal autophagy mechanisms and potential new therapeutic modalities for AMD based on autophagy modulation.

scholarly journals Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

2018 ◽  
Author(s):  
Youn-Shen Bee ◽  
Yi‐Ling Ma ◽  
Jinying Chen ◽  
Pei-Jhen Tsai ◽  
Shwu-Jiuan Sheu ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Aortic Ring ◽  
Age Related Macular Degeneration ◽  
Pathological Feature ◽  
Fundus Fluorescein Angiography ◽  
Age Related ◽  
Topical Applications

Choroidal neovascularization (CNV) is a key pathological feature of several of the leading causes of vision loss including neovascular age-related macular degeneration. Here we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation and migration of endothelial cells, and suppressed vascular sprouting from rat aortic ring explants. In rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10μg and 20μg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in the groups of rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10μg/mL and 20μg/mL of CAD27 installed, respectively). Retinal function was unaffected, as measured using electroretinography in both groups received interareal injection or topical applications of CAD27 at least for 9 days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in the diseases such as neovascular age-related macular degeneration.

scholarly journals Age-Related Macular Degeneration Revisited: From Pathology and Cellular Stress to Potential Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Majda Hadziahmetovic ◽  
Goldis Malek
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Clinical Care ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Impact

Age-related macular degeneration (AMD) is a neurodegenerative disease of the aging retina, in which patients experience severe vision loss. Therapies available to patients are limited and are only effective in a sub-population of patients. Future comprehensive clinical care depends on identifying new therapeutic targets and adopting a multi-therapeutic approach. With this goal in mind, this review examines the fundamental concepts underlying the development and progression of AMD and re-evaluates the pathogenic pathways associated with the disease, focusing on the impact of injury at the cellular level, with the understanding that critical assessment of the literature may help pave the way to identifying disease-relevant targets. During this process, we elaborate on responses of AMD vulnerable cells, including photoreceptors, retinal pigment epithelial cells, microglia, and choroidal endothelial cells, based on in vitro and in vivo studies, to select stressful agents, and discuss current therapeutic developments in the field, targeting different aspects of AMD pathobiology.

The Challenges of Treating Neovascular Age-Related Macular Degeneration

2021 ◽  
Author(s):  
Marlene Hollaus ◽  
Wolf Bühl ◽  
Ursula Schmidt-Erfurth ◽  
Stefan Sacu
Keyword(s):  
Health Care ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Health Care Systems ◽  
Developed Countries ◽  
Modern Medicine ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Effective Form ◽  
Care Systems

AbstractAge-related macular degeneration (AMD) is one of the main causes of visual impairment and blindness in patients over 60 years in developed countries. Whilst no effective form of therapy is available for the dry form of AMD, intravitreal application of anti-VEGF substances is able to prevent the progression of neovascular AMD (nAMD) in most cases. Aside from the drugs ranibizumab, aflibercept and brolucizumab, other agents such as bevacizumab are often used off-label in order to save expense. The treatment intervals have also been refined, so as to reduce the burden on patients and health care systems. After fixed injection intervals, the pro re nata-regimen has been developed. Each month, it is decided whether the patient receives intravitreal injections based on fixed criteria. In the treat and extend-protocol, patients receive injections on each visit, but the intervals between injections vary due to the clinical outcomes. The observe-and-plan regime allows scheduling of the injection intervals in blocks, for three consecutive injections at a time. However, results of real-world studies were not able to reproduce those obtained in the pivotal studies. A high number of visits and fear of the injection procedure impose a burden on patients, that is mostly accepted due to fear of vision loss. Caregivers also complain of loss of productivity and income from having to provide regular support to patients. Health care systems worldwide are affected by increasing treatment numbers and the costs involved. The treatment of nAMD constitutes an achievement for modern medicine. However, despite the challenges, it must be evaluated and reviewed repeatedly in order to provide the best therapy for patients.

scholarly journals Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

2018 ◽  
Author(s):  
Youn-Shen Bee ◽  
Jinying Chen ◽  
Pei-Jhen Tsai ◽  
Shwu-Jiuan Sheu ◽  
Hsiu-Chen Lin ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Aortic Ring ◽  
Age Related Macular Degeneration ◽  
Pathological Feature ◽  
Fundus Fluorescein Angiography ◽  
Age Related ◽  
Topical Applications

Choroidal neovascularization (CNV) is a key pathological feature of several of the leading causes of vision loss including neovascular age-related macular degeneration. Here we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation and migration of endothelial cells, and suppressed vascular sprouting from rat aortic ring explants. In rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10μg and 20μg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in the groups of rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10μg/mL and 20μg/mL of CAD27 installed, respectively). Retinal function was unaffected, as measured using electroretinography in both groups received interareal injection or topical applications of CAD27 at least for 9 days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in the diseases such as neovascular age-related macular degeneration.

scholarly journals Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Madhvi Menon ◽  
Shahin Mohammadi ◽  
Jose Davila-Velderrain ◽  
Brittany A. Goods ◽  
Tanina D. Cadwell ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Single Cell ◽  
Association Studies ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Genome Wide Association Studies ◽  
Human Retina ◽  
Age Related

Abstract Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.

scholarly journals Autophagy Genes for Wet Age-Related Macular Degeneration in a Finnish Case-Control Study

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1318
Author(s):  
Jussi J. Paterno ◽  
Ali Koskela ◽  
Juha M.T. Hyttinen ◽  
Elina Vattulainen ◽  
Ewelina Synowiec ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Retinal Pigment ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Cumulative Number ◽  
Sequestosome 1 ◽  
Anti Vegf ◽  
Age Related ◽  
Wet Amd

Age-related macular degeneration is an eye disease that is the main cause of legal blindness in the elderly in developed countries. Despite this, its pathogenesis is not completely known, and many genetic, epigenetic, environmental and lifestyle factors may be involved. Vision loss in age-related macular degeneration (AMD) is usually consequence of the occurrence of its wet (neovascular) form that is targeted in the clinic by anti-VEGF (vascular endothelial growth factor) treatment. The wet form of AMD is associated with the accumulation of cellular waste in the retinal pigment epithelium, which is removed by autophagy and the proteosomal degradation system. In the present work, we searched for the association between genotypes and alleles of single nucleotide polymorphisms (SNPs) of autophagy-related genes and wet AMD occurrence in a cohort of Finnish patients undergoing anti-VEGF therapy and controls. Additionally, the correlation between treatment efficacy and genotypes was investigated. Overall, 225 wet AMD patients and 161 controls were enrolled in this study. Ten SNPs (rs2295080, rs11121704, rs1057079, rs1064261, rs573775, rs11246867, rs3088051, rs10902469, rs73105013, rs10277) in the mTOR (Mechanistic Target of Rapamycin), ATG5 (Autophagy Related 5), ULK1 (Unc-51-Like Autophagy Activating Kinase 1), MAP1LC3A (Microtubule Associated Protein 1 Light Chain 3 α), SQSTM1 (Sequestosome 1) were analyzed with RT-PCR-based genotyping. The genotype/alleles rs2295080-G, rs11121704-C, rs1057079-C and rs73105013-T associated with an increased, whereas rs2295080-TT, rs2295080-T, rs11121704-TT, rs1057079-TT, rs1057079-T, rs573775-AA and rs73105013-C with a decreased occurrence of wet AMD. In addition, the rs2295080-GG, rs2295080-GT, rs1057079-TT, rs11246867-AG, rs3088051-CC and rs10277-CC genotypes were a positively correlated cumulative number of anti-VEGF injections in 2 years. Therefore, variability in autophagy genes may have an impact on the risk of wet AMD occurrence and the efficacy of anti-VEGF treatment.

scholarly journals Genetic Basis of Age-related Macular Degeneration

2011 ◽  
Vol 04 (02) ◽  
pp. 119
Author(s):  
Mohammad Othman ◽  
Kari Branham ◽  
John R Heckenlively ◽  
◽  
◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complex Disease ◽  
Vision Loss ◽  
Association Studies ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Factors Affecting ◽  
Age Related ◽  
Genome Wide

Age-related macular degeneration (AMD) is the main cause of vision loss and impairment in the aging population in developed countries. It is clinically and genetically a complex disease with both environmental and genetic factors affecting the outcome of the disease. Other than the wet type of AMD, there is no treatment for the other forms of AMD. It is estimated that the number of AMD patients will double in the next decade, which will have a significant financial impact on the health system and will compete for health dollars. Understanding the role of genetics in the development of AMD is paramount to help with diagnosis and future treatment. Over the past few years, we have studied the genetics of AMD and reported modest to significant association between AMD and several genes including CFH, ARMS2, TLR4 and ApoE. Our recent genome-wide association studies confirmed these AMD susceptibility loci in addition to other genes in the complement system (C2, C3, CFB and CFI). Recent studies identified new loci near TIMP3 and HDL influencing susceptibility to AMD.

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