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 Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Samuel Abokyi ◽  
Chi-Ho To ◽  
Tim T. Lam ◽  
Dennis Y. Tse
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Macular Degeneration ◽  
Molecular Mechanisms ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Vascular Endothelial ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

scholarly journals Experimental Models in Neovascular Age Related Macular Degeneration

2020 ◽  
Vol 21 (13) ◽  
pp. 4627
Author(s):  
Olivia Rastoin ◽  
Gilles Pagès ◽  
Maeva Dufies
Keyword(s):  
Macular Degeneration ◽  
Experimental Models ◽  
Age Related Macular Degeneration ◽  
Vascular Endothelial ◽  
In Vivo Models ◽  
Age Related ◽  
Decoy Receptors ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review.

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 Oral Delivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses Pathological Choroid Neovascularization

2020 ◽  
Vol 21 (2) ◽  
pp. 410 ◽  
Author(s):  
Valeria Tarallo ◽  
Emanuela Iaccarino ◽  
Valeria Cicatiello ◽  
Riccardo Sanna ◽  
Menotti Ruvo ◽  
...  
Keyword(s):  
Intravitreal Injection ◽  
Oral Delivery ◽  
Age Related Macular Degeneration ◽  
Preclinical Model ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Systemic Delivery ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is the primary cause of blindness in advanced countries. Repeated intravitreal delivery of anti-vascular endothelial growth factor (VEGF) agents has represented an important advancement for the therapy of wet AMD with significative results in terms of blindness prevention and partial vision restore. Nonetheless, some patients are not responsive or do not attain significant visual improvement, intravitreal injection may cause serious complications and important side effects have been reported for the prolonged block of VEGF-A. In order to evaluate new anti-angiogenic strategies, we focused our attention on VEGF receptor 1 (VEGFR1) developing a specific VEGFR-1 antagonist, a tetrameric tripeptide named inhibitor of VEGFR 1 (iVR1). We have evaluated its anti-angiogenic activity in the preclinical model of AMD, the laser-induced choroid neovascularization (CNV). iVR1 is able to potently inhibit CNV when delivered by intravitreal injection. Surprisingly, it is able to significantly reduce CNV also when delivered by gavage. Our data show that the specific block of VEGFR1 in vivo represents a valid alternative to the block of VEGF-A and that the inhibition of the pathological neovascularization at ocular level is also possible by systemic delivery of compounds not targeting VEGF-A.

scholarly journals Review of intravitreal vascular endothelial growth factor inhibitor toxicity and report of collapsing focal and segmental glomerulosclerosis with thrombotic microangiopathy in patient with age-related macular degeneration

2021 ◽  
Author(s):  
Gautam Phadke ◽  
Ramy M Hanna ◽  
Antoney Ferrey ◽  
Everardo Arias Torres ◽  
Anjali Singla ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Macular Degeneration ◽  
Case Reports ◽  
Age Related Macular Degeneration ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Segmental Glomerulosclerosis ◽  
Age Related ◽  
Endothelial Growth Factor

Abstract Intravitreal vascular endothelial growth factor (VEGF) receptor blockade is used for a variety of retinal pathologies. These include age-related macular degeneration (AMD), diabetic macular edema (DME) and central retinal vein obstruction. Reports of absorption of intravitreal agents into systemic circulation have increased in number and confirmation of depletion of VEGF has been confirmed. Increasingly there are studies and case reports showing worsening hypertension, proteinuria, renal dysfunction and glomerular disease. The pathognomonic findings of systemic VEGF blockade, thrombotic microangiopathies (TMAs), are also being increasingly reported. One lesion that occurs in conjunction with TMAs that has been described is collapsing focal segmental glomerulosclerosis (cFSGS). cFSGS has been postulated to occur due to TMA-induced chronic glomerular hypoxia. In this updated review we discuss the mechanistic, pharmacological, epidemiological and clinical evidence of intravitreal VEGF toxicity. We review cases of biopsy-proven toxicity presented by our group and other investigators. We also present the third reported case of cFSGS in the setting of intravitreal VEGF blockade with a chronic TMA component that was crucially found on biopsy. This patient is a 74-year-old nondiabetic male receiving aflibercept for AMD. Of the two prior cases of cFSGS in the setting of VEGF blockade, one had AMD and the other had DME. This case solidifies the finding of cFSGS and its association with chronic TMA as a lesion that may be frequently encountered in patients receiving intravitreal VEGF inhibitors.

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