Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.

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A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

Nutrients ◽

10.3390/nu13072441 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2441

Author(s):

Drake W. Lem ◽

Dennis L. Gierhart ◽

Pinakin Gunvant Davey

Keyword(s):

Diabetic Retinopathy ◽

Vision Loss ◽

Therapeutic Potential ◽

Microvascular Disease ◽

Age Related Macular Degeneration ◽

Cell Degeneration ◽

Neuroprotective Effects ◽

Age Related ◽

Induced Changes ◽

Dietary Carotenoid

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

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Introduction to the multi-author review on macular degeneration

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03418-5 ◽

2020 ◽

Vol 77 (5) ◽

pp. 779-780 ◽

Cited By ~ 1

Author(s):

Anu Kauppinen

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

The Elderly ◽

Developed Countries ◽

Age Related Macular Degeneration ◽

Age Related ◽

Severe Vision Loss ◽

Author Review ◽

Dry Amd ◽

Endothelial Growth Factor

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

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Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress

International Journal of Ophthalmology ◽

10.18240/ijo.2021.08.19 ◽

2021 ◽

Vol 14 (8) ◽

pp. 1260-1273

Author(s):

Zi-Yan Cai ◽

◽

Ke Liu ◽

Xuan-Chu Duan ◽

◽

...

Keyword(s):

Oxidative Stress ◽

Vision Loss ◽

Eye Diseases ◽

The Body ◽

Age Related Macular Degeneration ◽

Therapeutic Effects ◽

Related Factor ◽

Classical Pathway ◽

Age Related ◽

Important Relationship

Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.

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Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2019-000398 ◽

2019 ◽

Vol 4 (1) ◽

pp. e000398 ◽

Cited By ~ 14

Author(s):

Saira Khanna ◽

Rahul Komati ◽

David A Eichenbaum ◽

Ishani Hariprasad ◽

Thomas A Ciulla ◽

...

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Disease Process ◽

Age Related Macular Degeneration ◽

Anti Vegf ◽

Age Related ◽

Optimal Dosing ◽

Comparative Review ◽

Dosing Strategies ◽

Endothelial Growth Factor

Age-related macular degeneration is the leading cause of vision loss in the developed world, with the expected number of affected elderly individuals reaching 17.8 million. Antivascular endothelial growth factor (anti-VEGF) injection therapy has been instrumental in treating a disease process that was previously thought to be untreatable. Over the past two decades, landmark studies have demonstrated the efficacy of different anti-VEGF medications and investigated the optimal dosing regimen and delivery mechanism to increase overall vision and minimise patient burden. In this review, we outline landmark neovascular age-related macular degeneration clinical trials that have demonstrated level 1 evidence for its usage or have contributed to the understanding of how to dose these agents.

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Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin

eLife ◽

10.7554/elife.54056 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 10

Author(s):

Ross O Smith ◽

Takeshi Ninchoji ◽

Emma Gordon ◽

Helder André ◽

Elisabetta Dejana ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Vascular Permeability ◽

Geographic Atrophy ◽

Eye Diseases ◽

Age Related Macular Degeneration ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Oxygen Induced Retinopathy ◽

Age Related ◽

Endothelial Growth Factor

Edema stemming from leaky blood vessels is common in eye diseases such as age-related macular degeneration and diabetic retinopathy. Whereas therapies targeting vascular endothelial growth factor A (VEGFA) can suppress leakage, side-effects include vascular rarefaction and geographic atrophy. By challenging mouse models representing different steps in VEGFA/VEGF receptor 2 (VEGFR2)-induced vascular permeability, we show that targeting signaling downstream of VEGFR2 pY949 limits vascular permeability in retinopathy induced by high oxygen or by laser-wounding. Although suppressed permeability is accompanied by reduced pathological neoangiogenesis in oxygen-induced retinopathy, similarly sized lesions leak less in mutant mice, separating regulation of permeability from angiogenesis. Strikingly, vascular endothelial (VE)-cadherin phosphorylation at the Y685, but not Y658, residue is reduced when VEGFR2 pY949 signaling is impaired. These findings support a mechanism whereby VE-cadherin Y685 phosphorylation is selectively associated with excessive vascular leakage. Therapeutically, targeting VEGFR2-regulated VE-cadherin phosphorylation could suppress edema while leaving other VEGFR2-dependent functions intact.

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Nanotechnology for Age-Related Macular Degeneration

Pharmaceutics ◽

10.3390/pharmaceutics13122035 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2035

Author(s):

Bo Yang ◽

Ge Li ◽

Jiaxin Liu ◽

Xiangyu Li ◽

Shixin Zhang ◽

...

Keyword(s):

Drug Delivery ◽

Gene Therapy ◽

Macular Degeneration ◽

Vision Loss ◽

Cumulative Risk ◽

Age Related Macular Degeneration ◽

Delivery Methods ◽

Age Related ◽

Therapy Strategies ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is a degenerative eye disease that is the leading cause of irreversible vision loss in people 50 years and older. Today, the most common treatment for AMD involves repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, the existing expensive therapies not only cannot cure this disease, they also produce a variety of side effects. For example, the number of injections increases the cumulative risk of endophthalmitis and other complications. Today, a single intravitreal injection of gene therapy products can greatly reduce the burden of treatment and improve visual effects. In addition, the latest innovations in nanotherapy provide the best drug delivery alternative for the treatment of AMD. In this review, we discuss the development of nano-drug delivery systems and gene therapy strategies for AMD in recent years. In addition, we discuss some novel targeting strategies and the potential application of these delivery methods in the treatment of AMD. Finally, we also propose that the combination of CRISPR/Cas9 technology with a new non-viral delivery system may be promising as a therapeutic strategy for the treatment of AMD.

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Pegaptanib for Neovascular Age-Related Macular Degeneration

50 Studies Every Ophthalmologist Should Know ◽

10.1093/med/9780190050726.003.0039 ◽

2020 ◽

pp. 239-244

Author(s):

Alan D. Penman ◽

Kimberly W. Crowder ◽

William M. Watkins

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Age Related Macular Degeneration ◽

Vascular Endothelial ◽

Efficacy And Safety ◽

Neovascular Amd ◽

Ocular Neovascularization ◽

Age Related ◽

Discontinue Therapy ◽

Endothelial Growth Factor

The VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) study comprised two concurrent randomized, double-masked, sham-controlled clinical trials to evaluate the efficacy and safety of a second year of treatment with pegaptanib sodium (an anti-vascular endothelial growth factor [VEGF] agent) in patients with neovascular age-related macular degeneration (AMD). In combined analyses, 88% of patients were re-randomized at week 54, and 89% were assessed at week 102. At week 54, those initially assigned to pegaptanib were re-randomized to continue or discontinue therapy for 48 more weeks (8 injections). Those initially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. The study showed that in patients with a diverse mix of neovascular AMD presentations, treatment with pegaptanib every 6 weeks for 2 years reduced the risk of vision loss regardless of lesion composition or size; this benefit was maintained during year 2.

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The prevalence of eye diseases in the elderly population is a global problem of modernity

Health Care of the Russian Federation ◽

10.47470/0044-197x-2021-65-1-62-68 ◽

2021 ◽

Vol 65 (1) ◽

pp. 62-68

Author(s):

Dmitry A. Konyaev ◽

Evgenia B. Popova ◽

Anton A. Titov ◽

Nikolay M. Agarkov ◽

Maksim M. Yablokov ◽

...

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Practical Importance ◽

Age Groups ◽

The Elderly ◽

Eye Diseases ◽

Age Related Macular Degeneration ◽

Scientific Review ◽

Age Related ◽

High Prevalence

The priority problem of various industrial and developing countries, which largely determine the health of the population and, above all, older age groups, is currently eye diseases. Most modern researchers consider age-related macular degeneration, glaucoma, and cataracts to be eye diseases. Socially significant eye diseases have a high prevalence and are the leading cause of blindness in various countries. Authors analyzed the prevalence of glaucoma, age-related macular degeneration, and cataracts according to domestic and foreign publications in recent years. The results of the studies considered in the scientific review indicate a continuing gain in socially significant eye diseases, the frequency of which increases with age. The high incidence of the studied pathology is observed in China, India, and Russia. The study shows socially significant eye diseases to be the most critical problem in various countries, including the Russian Federation. The relevance of this pathology will increase due to the ongoing aging of the population and an increase in their share in the demographic structure of many states. The high prevalence of age-related macular degeneration, cataracts, and glaucoma leads to an increase in the number of people on the planet with complete or partial vision loss, which significantly disrupts their social functioning and requires significant financial costs for treatment and ensuring an acceptable level and quality of life. The data presented in the review and obtained results are of practical importance for the organization of monitoring of eye diseases and the development of an appropriate state and health strategy.

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Angiomatozna proliferacija v mrežnici in polipi v žilnici – fenotipa neovaskularizacij pri starostni degeneraciji makule

Slovenian Medical Journal ◽

10.6016/zdravvestn.1534 ◽

2016 ◽

Vol 85 (10) ◽

Author(s):

Tomislav Šarenac ◽

Mateja Groboljšek Žgavc ◽

Polona Jaki Mekjavič

Keyword(s):

Visual Acuity ◽

Vision Loss ◽

Developed Countries ◽

Age Related Macular Degeneration ◽

Repeated Treatment ◽

Vascular Endothelial ◽

Anti Vegf ◽

Age Related ◽

Type 3 ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is the leading cause of loss of visual acuity in developed countries. Antagonists of Vascular Endothelial Growth Factor (anti-VEGF) have been successfully used intravitreally in treating the neovascular form of this disease (nAMD) and limiting vision loss. With the latest developments in multimodal imaging we can discern multiple types of neovascularization, some of which have an unusual course, despite treatment with anti-VEGF. Indocianine green angiography (ICGA) and optical coherence tomography (OCT) have been used to distinguish two special forms of nARMD, i.e., retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy (PCV). RAP appears in 10–15 % of newly discovered nARMD, usually in older patients and is also known as type 3 neovascularisation, which starts intraretinally. It responds well to anti-VEGF. However, it requires closer monitoring, since in 75 % of patients it requires repeated treatment. In contrast, PCV evolves in the choroid and typically causes hemorrhagic exudative maculopathy, which is relatively unresponsive to anti-VEGF. It appears in 4–14 % of nAMD, and in somewhat younger patients. It requires a specifc approach to treatment, combining anti-VEGF with laser therapy, and close monitoring.Although PCV and RAP are less common forms of nARMD, we should use and properly interpret FA, ICGA and OCT in order to initiate recommended treatments and follow-up. Herewith we can lessen the adverse impact on the visual acuity and increase the quality of life of our patients.

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Features of angiogenesis in eye diseases

RUDN Journal of Medicine ◽

10.22363/2313-0245-2021-25-2-106-113 ◽

2021 ◽

Vol 25 (2) ◽

pp. 106-113

Author(s):

T. A. Khalimov

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Macular Degeneration ◽

Transforming Growth Factor ◽

Eye Diseases ◽

Age Related Macular Degeneration ◽

Published Data ◽

Vascular Endothelial ◽

Age Related ◽

Endothelial Growth Factor

Based on the analysis of published data, the review provides information on the role and mechanisms of angiogenesis in the development of eye diseases. It has been shown that the developing inflammatory process associated with infections or damage to the organ of vision almost always leads to the appearance of newly formed vessels in the avascular cornea. The progression, in particular, of age-related macular degeneration is associated with the immune-mediated development of angiogenesis processes. A key inducer of angiogenesis is vascular endothelial growth factor (VEGF), whose activity can be enhanced by a number of pro-inflammatory cytokines (tumor necrosis factor alpha, TNF-), growth (fibroblast growth factor, FGF) and transforming factors (transforming growth factor beta, TGF- ). In addition, VEGF overproduction is mediated by an imbalance of pro-angiogenic (angiogenin) and anti-angiogenic (angiostatin, vasostatin, endostatin; tissue inhibitors of matrix metalloproteinases) factors. Antiangiogenic activity based on inhibition of vascular endothelial growth factor (VEGF) has been successfully used in the treatment of a number of eye diseases, such as exudative age-related macular degeneration and diabetic macular edema, the pathogenesis of which is based on the growth of newly formed vessels. The review presents information on the main anti-angiogenic drugs for intravitreal administration, used in ophthalmology.

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