scholarly journals Promiscuous Chemokine Antagonist (BKT130) Suppresses Laser-Induced Choroidal Neovascularization by Inhibition of Monocyte Recruitment

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Shira Hagbi-Levi ◽  
Michal Abraham ◽  
Liran Tiosano ◽  
Batya Rinsky ◽  
Michelle Grunin ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Ex Vivo ◽  
Mononuclear Phagocytes ◽  
Age Related Macular Degeneration ◽  
Therapeutic Modality ◽  
Mrna Levels ◽  
Age Related ◽  
Chemokine Signaling ◽  
Monocyte Recruitment

Background. Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. Methods. A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. Results. BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages’ proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. Conclusions. Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.

scholarly journals RESVEGA, a Nutraceutical Omega-3/Resveratrol Supplementation, Reduces Angiogenesis in a Preclinical Mouse Model of Choroidal Neovascularization

2021 ◽  
Vol 22 (20) ◽  
pp. 11023
Author(s):  
Flavie Courtaut ◽  
Virginie Aires ◽  
Niyazi Acar ◽  
Lionel Bretillon ◽  
Ida Chiara Guerrera ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Blind Spot ◽  
Pleiotropic Effect ◽  
Resistance Mechanisms ◽  
Age Related Macular Degeneration ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Proteomic Approach ◽  
Age Related

Age-related macular degeneration (AMD) is an eye disease that is characterized by damage to the central part of the retina, the macula, and that affects millions of people worldwide. At an advanced stage, a blind spot grows in the center of vision, severely handicapping patients with this degenerative condition. Despite therapeutic advances thanks to the use of anti-VEGF, many resistance mechanisms have been found to accentuate the visual deficit. In the present study, we explored whether supplementation with Resvega®, a nutraceutical formulation composed of omega-3 fatty acids and resveratrol, a well-known polyphenol in grapes, was able to counteract laser-induced choroidal neovascularization (CNV) in mice. We highlight that Resvega® significantly reduced CNV in mice compared with supplementations containing omega-3 or resveratrol alone. Moreover, a proteomic approach confirmed that Resvega® could counteract the progression of AMD through a pleiotropic effect targeting key regulators of neoangiogenesis in retina cells in vivo. These events were associated with an accumulation of resveratrol metabolites within the retina. Therefore, a supplementation of omega-3/resveratrol could improve the management or slow the progression of AMD in patients with this condition.

scholarly journals CasRx-mediated RNA targeting prevents choroidal neovascularization in a mouse model of age-related macular degeneration

2020 ◽  
Vol 7 (5) ◽  
pp. 835-837 ◽  
Author(s):  
Changyang Zhou ◽  
Xinde Hu ◽  
Cheng Tang ◽  
Wenjia Liu ◽  
Shaoran Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Age Related Macular Degeneration ◽  
Proof Of Concept ◽  
Rna Transcripts ◽  
Age Related ◽  
Rna Targeting

Summary RNA-targeting CRISPR system Cas13 offers an efficient approach for manipulating RNA transcripts in vitro. In this perspective, we provide a proof-of-concept demonstration that Cas13-mediated Vegfa knockdown in vivo could prevent the development of laser-induced CNV in mouse model of Age-related macular degeneration.

scholarly journals Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration

2021 ◽  
Vol 22 (8) ◽  
pp. 3893
Author(s):  
Hye Cheong Koo ◽  
Yi-Yong Baek ◽  
Jun-Sup Choi ◽  
Young-Myeong Kim ◽  
Bokyung Sung ◽  
...  
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Vegf Receptor ◽  
Age Related ◽  
Human Plasminogen ◽  
Endothelial Growth Factor

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.

scholarly journals Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

2018 ◽  
Author(s):  
Sardar Pasha Sheik Pran Babu ◽  
Kamakshi Sishtla ◽  
Rania S. Sulaiman ◽  
Bomina Park ◽  
Trupti Shetty ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ex Vivo ◽  
Age Related Macular Degeneration ◽  
Lesion Volume ◽  
Ocular Neovascularization ◽  
Age Related ◽  
Promising Therapeutic Approach ◽  
Dna Binding Assay

AbstractOcular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-κB and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1’s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 μM, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a GI50APX2009: 26 μM, APX2014: 5.0 μM). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-κB activation and downstream targets.Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p< 0.0001, ANOVA with Dunnett’s post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesisin vitroandex vivo, and APX2009 is an effective systemic therapy for CNVin vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

scholarly journals Hypoxia Inhibits Subretinal Inflammation Resolution Thrombospondin-1 Dependently

2022 ◽  
Vol 23 (2) ◽  
pp. 681
Author(s):  
Sara Touhami ◽  
Fanny Béguier ◽  
Tianxiang Yang ◽  
Sébastien Augustin ◽  
Christophe Roubeix ◽  
...  
Keyword(s):  
Ambient Air ◽  
Mononuclear Phagocytes ◽  
Age Related Macular Degeneration ◽  
Human Monocytes ◽  
Age Related ◽  
Systemic Hypoxia ◽  
Thrombospondin 1 ◽  
Inflammation Resolution

Hypoxia is potentially one of the essential triggers in the pathogenesis of wet age-related macular degeneration (wetAMD), characterized by choroidal neovascularization (CNV) which is driven by the accumulation of subretinal mononuclear phagocytes (MP) that include monocyte-derived cells. Here we show that systemic hypoxia (10% O2) increased subretinal MP infiltration and inhibited inflammation resolution after laser-induced subretinal injury in vivo. Accordingly, hypoxic (2% O2) human monocytes (Mo) resisted elimination by RPE cells in co-culture. In Mos from hypoxic mice, Thrombospondin 1 mRNA (Thbs1) was most downregulated compared to normoxic animals and hypoxia repressed Thbs-1 expression in human monocytes in vitro. Hypoxic ambient air inhibited MP clearance during the resolution phase of laser-injury in wildtype animals, but had no effect on the exaggerated subretinal MP infiltration observed in normoxic Thbs1−/−-mice. Recombinant Thrombospondin 1 protein (TSP-1) completely reversed the pathogenic effect of hypoxia in Thbs1−/−-mice, and accelerated inflammation resolution and inhibited CNV in wildtype mice. Together, our results demonstrate that systemic hypoxia disturbs TSP-1-dependent subretinal immune suppression and promotes pathogenic subretinal inflammation and can be therapeutically countered by local recombinant TSP-1.

scholarly journals Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

2021 ◽  
Vol 9 ◽  
Author(s):  
Christine M. Sorenson ◽  
Yong-Seok Song ◽  
Ismail S. Zaitoun ◽  
Shoujian Wang ◽  
Barbara A. Hanna ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Choroidal Neovascularization ◽  
Cell Function ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Endothelial Cell Migration ◽  
Age Related

Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine’s ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities.

scholarly journals A new rat model of treatment-naive quiescent choroidal neovascularization induced by human VEGF165 overexpression

Biology Open ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. bio048736 ◽  
Author(s):  
Shan Liu ◽  
Antje K. Biesemeier ◽  
Alexander V. Tschulakow ◽  
Harsh V. Thakkar ◽  
Sylvie Julien-Schraermeyer ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Rat Model ◽  
Retinal Pigment ◽  
Basement Membranes ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
Short Term Treatment ◽  
Age Related ◽  
Treatment Naïve

ABSTRACTVascular endothelial growth factor (VEGF) is a crucial stimulator for choroidal neovascularization (CNV). Our aim was to develop a reproducible and valid treatment-naive quiescent CNV (i.e. without signs of exudation and with normal visual acuity) rat model by subretinal injection of an adeno-associated virus (AAV)-VEGFA165 vector. The CNV development was longitudinally followed up in vivo by scanning laser ophthalmoscopy/optical coherence tomography, fluorescein and Indocyanine Green angiographies and ex vivo by electron microscopy (EM) and immunohistochemistry. In total, 57 eyes were analysed. In vivo, a quiescent CNV was observed in 93% of the eyes 6 weeks post-transduction. In EM, CNV vessels with few fenestrations, multi-layered basement membranes and bifurcation of endothelial cells were observed sharing the human CNV features. Human VEGF overexpression, multi-layered retinal pigment epithelium (RPE) (RPE65) and macrophages/activated microglia (Iba1) were also detected. In addition, 19 CNV eyes were treated for up to 3 weeks with bevacizumab. The retinal and CNV lesion thickness decreased significantly in bevacizumab-treated CNV eyes compared with untreated CNV eyes 1 week after the treatment. In conclusion, our experimental CNV resembles those seen in patients suffering from treatment-naive quiescent CNV in wet age-related macular degeneration (AMD), and responds to short-term treatment with bevacizumab. Our new model can, therefore, be used to test the long-term effect of new drugs targeting CNV under precisely-defined conditions.

scholarly journals Secreted Phosphoprotein 1 Expression in Retinal Mononuclear Phagocytes Links Murine to Human Choroidal Neovascularization

2021 ◽  
Vol 8 ◽  
Author(s):  
Anja Schlecht ◽  
Peipei Zhang ◽  
Julian Wolf ◽  
Adrian Thien ◽  
Dennis-Dominik Rosmus ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Myeloid Cells ◽  
Mononuclear Phagocytes ◽  
Age Related Macular Degeneration ◽  
Angiogenic Factor ◽  
Western World ◽  
Rna Seq ◽  
Age Related ◽  
Retinal Microglia ◽  
Secreted Phosphoprotein 1

Age-related macular degeneration (AMD) represents the most common cause of blindness in the elderly in the Western world. An impairment of the outer blood-retina barrier and a localized inflammatory microenvironment cause sprouting of choroidal neovascular membranes (CNV) in neovascular AMD that are in intimate contact with surrounding myeloid cells, such as retinal microglia, and ultimately lead to visual impairment. The discovery of novel target molecules to interfere with angiogenesis and inflammation is vital for future treatment approaches in AMD patients. To explore the transcriptional profile and the function of retinal microglia at sites of CNV, we performed a comprehensive RNA-seq analysis of retinal microglia in the mouse model of laser-induced choroidal neovascularization (mCNV). Here, we identified the angiogenic factor Osteopontin (Opn), also known as “secreted phosphoprotein 1” (Spp1), as one of the most highly expressed genes in retinal microglia in the course of CNV formation. We confirmed the presence of SPP1 at the lesion site in recruited retinal microglia in Cx3cr1CreER:Rosa26-tdTomato reporter mice by confocal microscopy and in whole retinal tissue lysates by ELISA highlighting a massive local production of SPP1. Inhibition of SPP1 by intravitreal injection of an anti-SPP1 antibody significantly increased the lesion size compared to IgG-treated control eyes. In line with our results in rodents, we found an increased SPP1 mRNA expression in surgically extracted human choroidal neovascular (hCNV) membranes by the quantitative RNA-seq approach of massive analysis of cDNA ends (MACE). Numerous IBA1+SPP1+ myeloid cells were detected in human CNV membranes. Taken together, these results highlight the importance of SPP1 in the formation of CNV and potentially offer new opportunities for therapeutic intervention by modulating the SPP1 pathway.

Tissue Translocation Device for Surgical Correction of Age-Related Macular Degeneration

2013 ◽  
Vol 7 (4) ◽  
Author(s):  
George Mathai ◽  
David Rosen ◽  
Shreyes Melkote ◽  
Timothy Olsen
Keyword(s):  
Shape Memory ◽  
Macular Degeneration ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Potential Method ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Age Related

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world in those over age 60. While this disorder is complex, the origin of injury appears to be at the level of the retinal pigment epithelium (RPE), Bruchs membrane, and inner choroid. A potential method to replace damaged tissue in AMD is to harvest healthy donor tissue (RPE-Bruchs-Choroid) from an eye and translocate it to the injured subretinal region. Such an autograft avoids immune mediated rejection and can theoretically restore function to the neurosensory retina (light sensitive part of the retina) by restoring the damaged tissue. Such a procedure requires the design of a device that mechanically supports the integrity of the graft while inside the eye, without injuring or disrupting the tissue. This paper presents the systematic design and manufacture of a thin shape memory foil-based tissue translocation device. The selected embodiment of the design uses thermal adhesion of the tissue to the foil surfaces for tissue support. The shape memory effect enables insertion of the device into the eye via a small incision. The device is manufactured using micromachining techniques and has been tested both ex vivo and in vivo with acceptable anatomic results.

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